Chronic Pain: Advanced Treatments

*From Conventional to Innovative Approaches for Pain Treatment*

of patient-controlled analgesia for patients with acute abdominal pain in the emergency department: A randomized trial. Academic Emergency

Medicine. 2012;**19**(4):370-377

2012;**19**(4):241-245

1997;**85**(1):130-134

1995;**20**(6):506-514

[46] Rahman NH, DeSilva T. The

effectiveness of patient control analgesia in the treatment of acute traumatic pain in the emergency department: A randomized controlled trial. European Journal of Emergency Medicine.

[47] Stacey BR, Rudy TE, Nelhaus D. Management of patient-controlled analgesia: A comparison of primary surgeons and a dedicated pain service. Anesthesia and Analgesia.

[48] Chumbley GM, Hall GM, Salmon P. Patient-controlled analgesia: An assessment by 200 patients. Anaesthesia. 1998;**53**(3):216-221

[49] Pritchard C, Smith JE, Creanor S, et al. The cost-effectiveness of patientcontrolled analgesia vs. standard care in patients presenting to the Emergency Department in pain, who are subsequently admitted to hospital. Anaesthesia. 2017;**72**(8):953-960

[50] Chan VW, Chung F, McQuestion M, Gomez M. Impact of patient-

controlled analgesia on required nursing time and duration of postoperative recovery. Regional Anesthesia.

**54**

**57**

**Chapter 5**

Joint Pain

chronic osteoarthritis pain.

growth factor

**1. Introduction**

*Hollis Krug*

**Abstract**

The Use of Neurotoxins for

Palliative Treatment of Chronic

Osteoarthritis is a significant public health problem and is rapidly increasing in prevalence with the aging population. Pain is the most disabling consequence of osteoarthritis. Treatment for pain is inadequate and needs to be addressed with new therapeutic modalities. Chronic pain is often the result of peripheral and central pain sensitization which reduces the pain threshold and increases the perceived pain response to noxious and even non-noxious stimuli. Neurotoxins can reduce this sensitization by various mechanisms and are a fertile area of research for the treatment of chronic pain. Botulinum toxins, vanilloids, and conotoxin have all been studied for the treatment of chronic pain. Botulinum toxins and vanilloids have the greatest potential as analgesics for chronic joint pain thus far. Monoclonal antibodies directed against nerve growth factor have also been developed for the treatment of chronic joint pain due to osteoarthritis. These antibodies are not technically neurotoxins but have significant analgesic potential. However, they may have undesirable side effects and are still being evaluated as possible therapies for

**Keywords:** osteoarthritis, chronic pain, arthritis, neurotoxins, anti-nerve

Chronic joint pain is a world-wide problem. Osteoarthritis (OA) is the most common cause of chronic joint pain and is increasing in prevalence. In the United States alone, osteoarthritis affects approximately 27 million adults and is expected to exceed 67 million by the year 2030 [1, 2]. Although disability due to osteoarthritis varies, pain is the most disabling symptom affecting OA patients [3, 4]. To date, there are no disease modifying treatments for osteoarthritis. Treatment goals are focused on relief of symptoms and minimizing disability. The direct costs of treatment of OA combined with the indirect costs due to lost wages are substantial. According to one estimate, this cost accounts for 2% of the annual gross domestic product [5, 6]. Management of chronic pain from OA is challenging. Non-pharmacologic options include education, exercise, weight reduction, acupuncture, and joint protection, but these practices are generally insufficient to provide joint pain relief. Pharmacologic options include systemic and intraarticular therapies [7]. Insufficient pain relief, intolerable drug side effects and drug interactions increase the risk-benefit ratio for

#### **Chapter 5**

## The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain

*Hollis Krug*

#### **Abstract**

Osteoarthritis is a significant public health problem and is rapidly increasing in prevalence with the aging population. Pain is the most disabling consequence of osteoarthritis. Treatment for pain is inadequate and needs to be addressed with new therapeutic modalities. Chronic pain is often the result of peripheral and central pain sensitization which reduces the pain threshold and increases the perceived pain response to noxious and even non-noxious stimuli. Neurotoxins can reduce this sensitization by various mechanisms and are a fertile area of research for the treatment of chronic pain. Botulinum toxins, vanilloids, and conotoxin have all been studied for the treatment of chronic pain. Botulinum toxins and vanilloids have the greatest potential as analgesics for chronic joint pain thus far. Monoclonal antibodies directed against nerve growth factor have also been developed for the treatment of chronic joint pain due to osteoarthritis. These antibodies are not technically neurotoxins but have significant analgesic potential. However, they may have undesirable side effects and are still being evaluated as possible therapies for chronic osteoarthritis pain.

**Keywords:** osteoarthritis, chronic pain, arthritis, neurotoxins, anti-nerve growth factor

#### **1. Introduction**

Chronic joint pain is a world-wide problem. Osteoarthritis (OA) is the most common cause of chronic joint pain and is increasing in prevalence. In the United States alone, osteoarthritis affects approximately 27 million adults and is expected to exceed 67 million by the year 2030 [1, 2]. Although disability due to osteoarthritis varies, pain is the most disabling symptom affecting OA patients [3, 4]. To date, there are no disease modifying treatments for osteoarthritis. Treatment goals are focused on relief of symptoms and minimizing disability. The direct costs of treatment of OA combined with the indirect costs due to lost wages are substantial. According to one estimate, this cost accounts for 2% of the annual gross domestic product [5, 6]. Management of chronic pain from OA is challenging. Non-pharmacologic options include education, exercise, weight reduction, acupuncture, and joint protection, but these practices are generally insufficient to provide joint pain relief. Pharmacologic options include systemic and intraarticular therapies [7]. Insufficient pain relief, intolerable drug side effects and drug interactions increase the risk-benefit ratio for

available pharmaceutical therapies [8]. Even surgical therapies for degenerative joint disease may not be effective. Knee joint lavage has been shown to be no more effective for alleviation of pain than placebo [9, 10].

In particular, end stage disease provides challenges for effective therapy. Opioids can sometimes be effective when other therapies have lost efficacy, but the use of narcotics for chronic pain is undesirable due to eventual dependence and loss of efficacy, the need for dose escalation to maintain effectiveness, and the rising problem of opioid abuse and overdose that has occurred since the use of longacting narcotics have been available [11]. In addition, unacceptable side effects, particularly in the elderly who are more likely to have end stage osteoarthritis pain, makes the use of opioids a poor choice [12]. Finally, opioids may not have any increased efficacy for chronic OA pain compared with non-narcotic therapies [13]. The efficacy of intra-articular treatments such as corticosteroids and hyaluronic acid preparations have not been clearly demonstrated. For this reason the American Academy of Orthopedic Surgeons recommends against viscosupplementation and felt the evidence to be inclusive regarding corticosteroid injections for osteoarthritis [14].

Surgical treatment for end stage osteoarthritis is limited. Total joint replacement is generally considered to be effective for short and long-term pain relief and usually achieves positive clinical and functional outcomes [15, 16]. However, surgical treatments are not without risk of complications. These include systemic complications such as pulmonary embolism, but also local complications such as dislocation of hips, wound and joint infection, periprosthetic fracture, aseptic loosening, patellar maltracking, rupture of the extensor mechanism, stiffness with reduced range of motion, heterotopic ossification, metal hypersensitivity, vascular injury or bleeding, or nerve palsy. Success rates vary but as many as 1 in 5 patients undergoing total knee arthroplasty (TKA) are not satisfied with the outcome [16]. Obese patients are at increased risk for complications following TKA. Pre-operative management including weight loss, optimization of diabetes treatment, venous thromboembolism prevention, and physical therapy can help to minimize these complications [17]. Even so, some individuals will not be surgical candidates. Clearly other options are needed for effective pain relief to minimize disability and optimize function in patients who are not candidates for surgery and for whom standard analgesics have not been helpful.

Palliative therapy is specialized medical care focused on providing relief from the symptoms and stress of a serious illness. The goal is to improve quality of life and enhance physical function, but without treating or attempting to cure the underlying disease. Palliative therapy for end stage osteoarthritis is a concept that has been explored but due to a lack of effective therapies has not been very successful [18].

#### **2. Neurobiology of chronic pain**

Pain is the result of nerves transmitting a noxious signal, usually the result of some sort of injury, to the brain where it is perceived as pain. This is an important signal for the organism experiencing the injury to withdraw or avoid the stimulus that is producing the pain. Chronic pain results when nociceptive systems are altered so that there is no longer a direct relationship between a noxious stimulus and pain perception. These alterations are due to plasticity of the nervous system whereby peripheral nerves become sensitized, or spinal cord neurons become increasingly excitable. Projections from the spinal cord to higher centers can result in changes to descending inhibitory controls that are initiated in the midbrain and brainstem. All these changes together tend to alter the perceived response to any

**59**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

ible and thus amenable to pharmacologic therapies [19].

stimulus and thus lead to persistent pain states. This plasticity appears to be revers-

Peripheral sensitization is thought to be the result of inflammation or nerve injury which alters nociceptive receptors causing increased intracellular calcium and activated intracellular protein kinase C and tyrosine kinases. These mediators phosphorylate sensory neuron-specific sodium channels and Transient Receptor Potential Vanilloid 1 (TRPV1) receptors causing a reduction in the depolarization threshold and reduced pain threshold. Nociceptive neurons themselves release chemical stimulants such as substance P (SP) and calcitonin gene-related peptide (CGRP) which amplify the local inflammatory response by interacting with local inflammatory cells and nearby blood vessels. This "neurogenic inflammation" causes vasodilation and edema, and increases local inflammation adding to peripheral sensitization [20]. Pharmacologic inhibition of this sensitization process is an attractive target for analgesia, as reducing sensitization would be expected to reduce the pain perception without eliminating the important pain defense mechanisms. Given the critical involvement of neuropeptides in the development of sensitization, the efficacy of neurotoxins was hypothesized for treatment of chronic pain.

There are eight serotypes of botulinum toxin. All are products of the bacterial genus *Clostridium*. Types A-G have been fully characterized and have varying durations of action, and enzymatic targets. They all cleave components of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) proteins. The inability of the disrupted SNARE proteins to bring the synaptic vesicle membrane and the terminal plasma membrane of the peripheral nerve in close proximity results in an inability of the two membranes to fuse and failure of the nerve to release neurotransmitter such as acetylcholine (ACh). This produces the dramatic paralytic activity of botulinum toxin [21]. The eighth serotype, H, has been recently described, but its gene sequence has been withheld due to public safety concerns since it is considered the deadliest substance in the world [22].

Botulinum toxins A and B have been used for some time to treat painful muscle dystonias such as torticollis. It was thought that the paralytic effect of the toxin on motor units in the dystonic muscle was responsible for the pain relief that accompanied this treatment. But it was observed that pain relief preceded the muscle weakness that was expected with these treatments. This observation led to early studies of the use of intra-articular onabotulinum toxin (Type A) for end stage osteoarthritis [23]. Subsequent similar studies have been done and summarized in meta-analyses and systematic reviews. Their findings suggest that even for end stage arthritis pain, intra-articular botulinum toxin has modest beneficial effects in patients with refractory joint pain [24–27]. Studies of shoulders and knees predominated but one study treated refractory ankle osteoarthritis pain and one treated refractory pain after total knee arthroplasty. Doses used were between 100 and 200 IU onabotulinum toxin A (BOTOX), 200–500 IU abobotulinum toxin A (Dysport) and 2500 IU rimabotulinum toxin B (Myobloc). Controls in these studies were variable ranging from triamcinolone to saline to unspecified placebo. Some studies used botulinum toxin diluted with lidocaine and compared to saline with lidocaine. One small study of 75 patients compared intra-articular (IA) botulinum toxin A to injection with 2 ml sodium hyaluronate in patients with symptomatic ankle OA and found no difference in effectiveness between the two interventions [28]. Since the American

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

**3. Botulinum toxins as analgesics**

**3.1 Botulinum toxin background and human studies**

#### *The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain DOI: http://dx.doi.org/10.5772/intechopen.84593*

*From Conventional to Innovative Approaches for Pain Treatment*

tive for alleviation of pain than placebo [9, 10].

osteoarthritis [14].

not been helpful.

**2. Neurobiology of chronic pain**

available pharmaceutical therapies [8]. Even surgical therapies for degenerative joint disease may not be effective. Knee joint lavage has been shown to be no more effec-

Surgical treatment for end stage osteoarthritis is limited. Total joint replacement is generally considered to be effective for short and long-term pain relief and usually achieves positive clinical and functional outcomes [15, 16]. However, surgical treatments are not without risk of complications. These include systemic complications such as pulmonary embolism, but also local complications such as dislocation of hips, wound and joint infection, periprosthetic fracture, aseptic loosening, patellar maltracking, rupture of the extensor mechanism, stiffness with reduced range of motion, heterotopic ossification, metal hypersensitivity, vascular injury or bleeding, or nerve palsy. Success rates vary but as many as 1 in 5 patients undergoing total knee arthroplasty (TKA) are not satisfied with the outcome [16]. Obese patients are at increased risk for complications following TKA. Pre-operative management including weight loss, optimization of diabetes treatment, venous thromboembolism prevention, and physical therapy can help to minimize these complications [17]. Even so, some individuals will not be surgical candidates. Clearly other options are needed for effective pain relief to minimize disability and optimize function in patients who are not candidates for surgery and for whom standard analgesics have

Palliative therapy is specialized medical care focused on providing relief from the symptoms and stress of a serious illness. The goal is to improve quality of life and enhance physical function, but without treating or attempting to cure the underlying disease. Palliative therapy for end stage osteoarthritis is a concept that has been explored but due to a lack of effective therapies has not been very successful [18].

Pain is the result of nerves transmitting a noxious signal, usually the result of some sort of injury, to the brain where it is perceived as pain. This is an important signal for the organism experiencing the injury to withdraw or avoid the stimulus that is producing the pain. Chronic pain results when nociceptive systems are altered so that there is no longer a direct relationship between a noxious stimulus and pain perception. These alterations are due to plasticity of the nervous system whereby peripheral nerves become sensitized, or spinal cord neurons become increasingly excitable. Projections from the spinal cord to higher centers can result in changes to descending inhibitory controls that are initiated in the midbrain and brainstem. All these changes together tend to alter the perceived response to any

In particular, end stage disease provides challenges for effective therapy. Opioids can sometimes be effective when other therapies have lost efficacy, but the use of narcotics for chronic pain is undesirable due to eventual dependence and loss of efficacy, the need for dose escalation to maintain effectiveness, and the rising problem of opioid abuse and overdose that has occurred since the use of longacting narcotics have been available [11]. In addition, unacceptable side effects, particularly in the elderly who are more likely to have end stage osteoarthritis pain, makes the use of opioids a poor choice [12]. Finally, opioids may not have any increased efficacy for chronic OA pain compared with non-narcotic therapies [13]. The efficacy of intra-articular treatments such as corticosteroids and hyaluronic acid preparations have not been clearly demonstrated. For this reason the American Academy of Orthopedic Surgeons recommends against viscosupplementation and felt the evidence to be inclusive regarding corticosteroid injections for

**58**

stimulus and thus lead to persistent pain states. This plasticity appears to be reversible and thus amenable to pharmacologic therapies [19].

Peripheral sensitization is thought to be the result of inflammation or nerve injury which alters nociceptive receptors causing increased intracellular calcium and activated intracellular protein kinase C and tyrosine kinases. These mediators phosphorylate sensory neuron-specific sodium channels and Transient Receptor Potential Vanilloid 1 (TRPV1) receptors causing a reduction in the depolarization threshold and reduced pain threshold. Nociceptive neurons themselves release chemical stimulants such as substance P (SP) and calcitonin gene-related peptide (CGRP) which amplify the local inflammatory response by interacting with local inflammatory cells and nearby blood vessels. This "neurogenic inflammation" causes vasodilation and edema, and increases local inflammation adding to peripheral sensitization [20]. Pharmacologic inhibition of this sensitization process is an attractive target for analgesia, as reducing sensitization would be expected to reduce the pain perception without eliminating the important pain defense mechanisms. Given the critical involvement of neuropeptides in the development of sensitization, the efficacy of neurotoxins was hypothesized for treatment of chronic pain.

#### **3. Botulinum toxins as analgesics**

#### **3.1 Botulinum toxin background and human studies**

There are eight serotypes of botulinum toxin. All are products of the bacterial genus *Clostridium*. Types A-G have been fully characterized and have varying durations of action, and enzymatic targets. They all cleave components of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) proteins. The inability of the disrupted SNARE proteins to bring the synaptic vesicle membrane and the terminal plasma membrane of the peripheral nerve in close proximity results in an inability of the two membranes to fuse and failure of the nerve to release neurotransmitter such as acetylcholine (ACh). This produces the dramatic paralytic activity of botulinum toxin [21]. The eighth serotype, H, has been recently described, but its gene sequence has been withheld due to public safety concerns since it is considered the deadliest substance in the world [22].

Botulinum toxins A and B have been used for some time to treat painful muscle dystonias such as torticollis. It was thought that the paralytic effect of the toxin on motor units in the dystonic muscle was responsible for the pain relief that accompanied this treatment. But it was observed that pain relief preceded the muscle weakness that was expected with these treatments. This observation led to early studies of the use of intra-articular onabotulinum toxin (Type A) for end stage osteoarthritis [23]. Subsequent similar studies have been done and summarized in meta-analyses and systematic reviews. Their findings suggest that even for end stage arthritis pain, intra-articular botulinum toxin has modest beneficial effects in patients with refractory joint pain [24–27]. Studies of shoulders and knees predominated but one study treated refractory ankle osteoarthritis pain and one treated refractory pain after total knee arthroplasty. Doses used were between 100 and 200 IU onabotulinum toxin A (BOTOX), 200–500 IU abobotulinum toxin A (Dysport) and 2500 IU rimabotulinum toxin B (Myobloc). Controls in these studies were variable ranging from triamcinolone to saline to unspecified placebo. Some studies used botulinum toxin diluted with lidocaine and compared to saline with lidocaine. One small study of 75 patients compared intra-articular (IA) botulinum toxin A to injection with 2 ml sodium hyaluronate in patients with symptomatic ankle OA and found no difference in effectiveness between the two interventions [28]. Since the American

Academy of Orthopedic Surgeons has stated in their evidence based guidelines for the treatment of OA of the knee that viscosupplementation cannot be recommended, this comparison may be less than appropriate [29].

Studies of IA botulinum toxin use in humans have not reported significant safety issues. Although weakness was initially a concern, it was not found in extensive safety evaluations [23, 26]. Since a single injection provides pain relief for up to 6 months, fewer injections may be required as compared to corticosteroid or viscosupplementation injections and therefore, the risk of infection is minimized.

#### **3.2 Botulinum toxin studies in preclinical models of joint pain**

In an effort to better understand the mechanism of action of pain relief seen with botulinum toxin and to precisely define functional outcomes, a variety of animal studies have been done (**Table 1**). Botulinum toxins have been given intraarticularly for joint pain in mice, rats and dogs. IA botulinum toxin appears to be effective for chronic arthritis pain but not acute joint pain in mice, supporting the idea that botulinum toxin reduces peripheral sensitization by inhibiting neuropeptide release in the periphery [30, 31]. Only one study evaluated efficacy of rimabotulinum toxin for osteoarthritis pain in mice and found that it reduced both spontaneous and evoked pain behaviors [32]. In dogs with chronic lameness due to stifle, hip or elbow osteoarthritis IA onabotulinum toxin produced improvement in several force platform variables including vertical impulse, peak vertical force and in the Helsinki chronic pain index compared to the placebo group after 12 weeks. The secondary outcomes of subjective pain score and the need for rescue analgesics were not significantly improved in the botulinum toxin treated group compared to placebo. No major adverse events were detected [33]. A second study in dogs designed to detect adverse effects of IA botulinum toxin compared toxin injection to placebo in healthy beagle dogs. This study evaluated dynamic and static weight bearing, range of motion, joint tenderness, synovial fluid, neurologic function and electrophysiologic recordings, and histopathology of joint structures and adjacent muscles and nerves. Intra-articular botulinum toxin A did not produce significant clinical, cytological, or histopathological adverse effects in healthy dogs, but based on the electrophysiological recordings that found low compound muscle action potentials in 2 dogs in the botulinum toxin injected limb, the authors concluded that toxin may spread from the joint, but that its clinical impact is probably low [34]. In rats with inflammatory arthritis of the temporal mandibular joint (TMJ) produced by immunization with bovine serum albumin (BSA) and subsequent intra-articular challenge with BSA, injecting the joint with botulinum toxin A significantly reduced nociceptive behaviors that resulted from IA injection of low dose formalin into these inflamed joints. These authors demonstrated that the trigeminal ganglion of botulinum A treated arthritic animals released less substance P (SP) and calcitonin gene related peptide (CGRP) than saline treated arthritic animals but glutamate release was not affected. Glutamate receptors AMPA and NMDA were also unchanged in botulinum treated ganglia compared to saline treated controls. Periarticular tissues from the arthritic TMJs released increased amounts of interleukin 1-β (IL-1β) and tumor necrosis factor α (TNFα). Treatment with botulinum toxin reduced IL-1β release but had no effect on TNFα [35]. In another study of rats with adjuvant-induced arthritis induced in the tibial-tarsal joint, mechanical and thermal hyperalgesia and TRPV1 expression in the L4-5 dorsal root ganglia (DRG) were measured. DRGs were also stained for the presence of cleaved synaptosomal-associated protein of 25 kDa (SNAP-25)—the cleavage product of botulinum toxin A—and for transient receptor potential vanilloid 1 and put TRPV1 in parentheses TRPV1 and CGRP. TRPV1 expression increased significantly in

**61**

**Table 1.**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

or sham injection

Outcome measured after 12 weeks

IA BoNT/A followed by pain induction with formalin injection

IA BoNT/A (dose ranging) compared to CFA alone and saline control

BiTox—unique nonparalyzing botulinum toxin molecule

of mice to express the conotoxin ω-conopeptide MVIIA vs. wild type

ACIA model in mice Genetic modification

IA BoNT/A vs. placebo

**Arthritis model Experiment Results Reference**

arthritis

IA BoNT vs. placebo No adverse clinical, cytological, or

to muscle

joint tenderness

behaviors in CFA arthritis, reduced spontaneous pain behavior in COL

Improved visual gait analysis, improved

Improved peak vertical force, improved

histopathological effects. Some EMG evidence for spread outside the joints

Significantly reduced pain behaviors, reduced SP and CGRP release, no change in glutamate release, reduced release of IL-1β but not TNFα

All pain outcomes improved in a dose dependent fashion. (Mechanical and thermal hyperalgesia) TRPV1 expression reduced but not transcription, thought due to the observed reduced movement of TRPV1

to the cell membrane

CFA induced swelling reduced, mechanical hyperalgesia but not thermal hyperalgesia reduced. No effect on acute pain from capsaicin or formalin but reduced secondary mechanical hyperalgesia after plantar capsaicin injection. Plantar incision pain response reduced after day 2. Reduced neuropathic pain in the SNI model

Pain was suppressed but joint inflammation was increased and more destructive in genetically modified mice

Helsinki chronic pain index

[30, 31]

[32]

[33]

[34]

[35]

[36]

[37]

[55]

Murine CFA, COL IA BoNT/A vs. sham Reduced spontaneous and evoked pain

the arthritic animals' DRGs and arthritic animals demonstrated mechanical and thermal hyperalgesia. Botulinum toxin A increased the paw withdrawal threshold and latency to both mechanical and thermal stimuli and reduced TRPV1 expression in a dose-dependent manner. TRPV1 transcription was likewise increased with Complete Freund's Adjuvant (CFA) induced arthritis but botulinum toxin A did not alter this increased transcription. Using immunofluorescent staining, these authors found that the increase in TRPV1 and CGRP co-expressing neurons which was the result of CFA arthritis was reduced by botulinum toxin in a dose dependent manner. Since botulinum toxin exerts its effects by cleaving SNAP-25 and thus preventing

*CFA—complete freund's adjuvant induced arthritis, COL—collagenase-induced osteoarthritis, BoNT/A onabotulinum toxin type A, BoNT/B—rimabotulinum toxin type B, BSA—bovine serum albumin, TMJ—temporal* 

*mandibular joint, SNI—spared nerve injury, ACIA—antigen and collagen-induced arthritis.*

*Preclinical studies of botulinum and other toxins as analgesics for arthritis pain.*

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

Murine COL IA BoNT/B vs. saline

Dog, OA, multiple

Healthy beagles (safety study)

Rat BSA TMJ inflammatory arthritis

joint

Rat CFA tibiotarsal

Rat CFA ankle arthritis Plantar injection of capsaicin and formalin and plantar incision as standardized pain models. Also included SNI model

joints


*onabotulinum toxin type A, BoNT/B—rimabotulinum toxin type B, BSA—bovine serum albumin, TMJ—temporal mandibular joint, SNI—spared nerve injury, ACIA—antigen and collagen-induced arthritis.*

#### **Table 1.**

*From Conventional to Innovative Approaches for Pain Treatment*

mended, this comparison may be less than appropriate [29].

**3.2 Botulinum toxin studies in preclinical models of joint pain**

Academy of Orthopedic Surgeons has stated in their evidence based guidelines for the treatment of OA of the knee that viscosupplementation cannot be recom-

issues. Although weakness was initially a concern, it was not found in extensive safety evaluations [23, 26]. Since a single injection provides pain relief for up to 6 months, fewer injections may be required as compared to corticosteroid or viscosupplementation injections and therefore, the risk of infection is minimized.

In an effort to better understand the mechanism of action of pain relief seen with botulinum toxin and to precisely define functional outcomes, a variety of animal studies have been done (**Table 1**). Botulinum toxins have been given intraarticularly for joint pain in mice, rats and dogs. IA botulinum toxin appears to be effective for chronic arthritis pain but not acute joint pain in mice, supporting the idea that botulinum toxin reduces peripheral sensitization by inhibiting neuropeptide release in the periphery [30, 31]. Only one study evaluated efficacy of rimabotulinum toxin for osteoarthritis pain in mice and found that it reduced both spontaneous and evoked pain behaviors [32]. In dogs with chronic lameness due to stifle, hip or elbow osteoarthritis IA onabotulinum toxin produced improvement in several force platform variables including vertical impulse, peak vertical force and in the Helsinki chronic pain index compared to the placebo group after 12 weeks. The secondary outcomes of subjective pain score and the need for rescue analgesics were not significantly improved in the botulinum toxin treated group compared to placebo. No major adverse events were detected [33]. A second study in dogs designed to detect adverse effects of IA botulinum toxin compared toxin injection to placebo in healthy beagle dogs. This study evaluated dynamic and static weight bearing, range of motion, joint tenderness, synovial fluid, neurologic function and electrophysiologic recordings, and histopathology of joint structures and adjacent muscles and nerves. Intra-articular botulinum toxin A did not produce significant clinical, cytological, or histopathological adverse effects in healthy dogs, but based on the electrophysiological recordings that found low compound muscle action potentials in 2 dogs in the botulinum toxin injected limb, the authors concluded that toxin may spread from the joint, but that its clinical impact is probably low [34]. In rats with inflammatory arthritis of the temporal mandibular joint (TMJ) produced by immunization with bovine serum albumin (BSA) and subsequent intra-articular challenge with BSA, injecting the joint with botulinum toxin A significantly reduced nociceptive behaviors that resulted from IA injection of low dose formalin into these inflamed joints. These authors demonstrated that the trigeminal ganglion of botulinum A treated arthritic animals released less substance P (SP) and calcitonin gene related peptide (CGRP) than saline treated arthritic animals but glutamate release was not affected. Glutamate receptors AMPA and NMDA were also unchanged in botulinum treated ganglia compared to saline treated controls. Periarticular tissues from the arthritic TMJs released increased amounts of interleukin 1-β (IL-1β) and tumor necrosis factor α (TNFα). Treatment with botulinum toxin reduced IL-1β release but had no effect on TNFα [35]. In another study of rats with adjuvant-induced arthritis induced in the tibial-tarsal joint, mechanical and thermal hyperalgesia and TRPV1 expression in the L4-5 dorsal root ganglia (DRG) were measured. DRGs were also stained for the presence of cleaved synaptosomal-associated protein of 25 kDa (SNAP-25)—the cleavage product of botulinum toxin A—and for transient receptor potential vanilloid 1 and put TRPV1 in parentheses TRPV1 and CGRP. TRPV1 expression increased significantly in

Studies of IA botulinum toxin use in humans have not reported significant safety

**60**

*Preclinical studies of botulinum and other toxins as analgesics for arthritis pain.*

the arthritic animals' DRGs and arthritic animals demonstrated mechanical and thermal hyperalgesia. Botulinum toxin A increased the paw withdrawal threshold and latency to both mechanical and thermal stimuli and reduced TRPV1 expression in a dose-dependent manner. TRPV1 transcription was likewise increased with Complete Freund's Adjuvant (CFA) induced arthritis but botulinum toxin A did not alter this increased transcription. Using immunofluorescent staining, these authors found that the increase in TRPV1 and CGRP co-expressing neurons which was the result of CFA arthritis was reduced by botulinum toxin in a dose dependent manner. Since botulinum toxin exerts its effects by cleaving SNAP-25 and thus preventing

release of neuropeptide by preventing fusion of vesicles with the terminal membrane, the presence of cleaved SNAP 25 localized with TRPV1 in the DRG was analyzed. Co-localization of cleaved SNAP-25 with TRPV1 in the botulinum toxin A group was clearly seen 5 days after botulinum toxin injection. This was not seen in the sham and CFA saline control groups. These authors speculated that botulinum toxin A may prevent TRPV1 expression on DRG neurons by inhibition of TRPV1 trafficking to the cell membrane after retrograde transport of botulinum toxin from the periphery to the DRG since the expression of the TRPV1 receptor has been shown to be dependent on exocytosis that requires interactions with proteins of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of SNAP-25 [36]. The presence of botulinum toxin in the DRG would prevent the SNARE complex from functioning normally to move TRPV1 to the cell membrane. A botulinum toxin A based molecule—BiTox—has been synthesized that is reported to retain neuronal silencing capacity without causing paralysis. This molecule reduces plasma extravasation and inflammatory edema but is not transported to the DRG ganglia or dorsal horn and does not inhibit pain behaviors in response to formalin or capsaicin and does not inhibit formalin-induced c-Fos expression in the dorsal horn. It was found to strongly reduce A-nociceptor mediated secondary mechanical hyperalgesia due to CFA joint inflammation or capsaicin injection and decreased hypersensitivity from nerve injury. The authors concluded that this botulinum toxin based molecule could reduce local release of neuromodulators from C fibers without impairing C nociceptive signaling function [37].

#### **4. Vanilloids as analgesics**

#### **4.1 Vanilloids and their receptors background**

Vanilloids such as capsaicin (the active ingredient in hot chili peppers) and resiniferatoxin (a product of the plant *Euphorbia resinifera*) were first notable for their ability to produce burning pain when administered topically. Later, both molecules were found to have analgesic potential and subsequent work identified the non-selective cation channel to which these compounds bind. This receptor was found to be located on the dorsal root and trigeminal ganglia of various species. Subsequent work identified the channel, allowed cloning and cDNA characterization, and revealed that the channel could be activated not only by vanilloids but also by heat suggesting a role in thermosensation. The receptor was named transient receptor potential vanilloid 1 (TRPV1) and other ligands were identified making it a transducer of many types of noxious stimuli [38].

Because of the variety of ligands, TRPV1 was considered a likely target for analgesia. Agonists such as vanilloids were noted to cause desensitization of these channels and in rodents as well as humans, pain behaviors could be alleviated with vanilloid treatment. TRPV1 knockout mice demonstrated reduced thermal hypersensitivity with inflammation. TRPV1 antagonists were shown to reverse pain behavior in rodents with a wide variety of painful conditions including inflammation, osteoarthritis and cancer. Both agonists and antagonists have been considered as analgesic therapies. Although systemic administration of vanilloids demonstrated analgesic efficacy in preclinical pain models, because of the undesirable systemic side effects of these compounds, most therapeutic trials have focused on local or topical administration of these compounds. Undesirable effects include hypotension, respiratory compromise and other negative effects on reflex pathways. Less pungent analogs were found to be less efficacious with respect to analgesia [38].

**63**

**Table 2.**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

**4.2 Vanilloids as analgesics—Human and pre-clinical studies**

In humans, current treatment of joint pain with vanilloids is limited to topical therapies. Pain relieving creams such as Zostrix® and patches such as Salonpas Hot Capsicum Patch® are available over the counter and contain capsaicin as the active ingredient. Multiple clinical trials have found modest benefit for osteoarthritis from low dose topical capsaicin [39–41]. More recently, a high dose 8% capsaicin patch has been approved for the treatment of post-herpetic neuralgia. According to the package insert, application of the patch requires careful adherence to application instructions by the health care professional and local anesthesia for the patient prior to application and systemic analgesics as needed in the post-application period. Interestingly, results from clinical trials of this drug for treatment of painful HIV

Resiniferatoxin (RTX) is an ultra-potent capsaicin (CAP) analogue [44], that is several thousand-fold more potent than CAP [45]. RTX in low concentrations produces a slow and sustained depolarization of membrane potential, preventing the generation of action potentials but causing less toxicity. A single IA injection in rats has been found to reduce hyperalgesia due to carrageenan induced joint pain [46]. RTX has been studied in clinical trials for other painful conditions. When given intravesicularly for interstitial cystitis and painful bladder syndrome, it did not improved overall symptoms of pain, urgency, frequency or nocturia [47, 48]. Adlea™ (4975) is another CAP analogue under development for the treatment of post-operative musculoskeletal pain, osteoarthritis and tendinopathy. Phase II trials of intra-articular injection of this compound were encouraging but no further clinical trials appear to have been performed [38]. Zucapsaicin (Civamide) is the cis-isomer of capsaicin, and functions as a TRPV1 blocker. Phase III trials have been done with topical civamide for OA knee pain [49]. This topical therapy is not absorbed systemically, is well tolerated, and produced significant improvement in Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical function score, pain score and subject global evaluation. Improvement was maintained for a year. This drug

Several TRPV1 antagonists have also been identified that act as analgesics [50]. Some are more selective than others, complete nonselectivity producing inhibition of all modes of TRPV1 activation (protons, heat and capsaicin). More selectivity

**Arthritis model Experiment Results Reference**

Significant reduction in pain behavior with RTX [46]

[50, 51]

[50, 52, 53]

treatment

47% reduction in weightbearing asymmetry. Prolonged benefit

Reduced loss of grip force within 1 hour and maintained up to 8 hours

IA RTX vs. vehicle given 24 hours after arthritis induction in a dose ranging study

A-425619 given IP in a dose range during acute inflammatory phase

orally

*IA—intra-articular, RTX—resiniferatoxin, MIA—monosodium iodoacetate.*

A-889425 and A-995662 given

*Preclinical studies of vanilloid agonists and antagonists as analgesics for arthritis pain.*

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

neuropathy did not show clinical benefit [42, 43].

has not yet been approved by the US FDA.

**4.3 TRPV1 antagonists as analgesics**

Rat carrageenaninduced acute joint

Rat MIA model early phase

Rat MIA model—late

pain

phase

*From Conventional to Innovative Approaches for Pain Treatment*

**4. Vanilloids as analgesics**

**4.1 Vanilloids and their receptors background**

transducer of many types of noxious stimuli [38].

release of neuropeptide by preventing fusion of vesicles with the terminal membrane, the presence of cleaved SNAP 25 localized with TRPV1 in the DRG was analyzed. Co-localization of cleaved SNAP-25 with TRPV1 in the botulinum toxin A group was clearly seen 5 days after botulinum toxin injection. This was not seen in the sham and CFA saline control groups. These authors speculated that botulinum toxin A may prevent TRPV1 expression on DRG neurons by inhibition of TRPV1 trafficking to the cell membrane after retrograde transport of botulinum toxin from the periphery to the DRG since the expression of the TRPV1 receptor has been shown to be dependent on exocytosis that requires interactions with proteins of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of SNAP-25 [36]. The presence of botulinum toxin in the DRG would prevent the SNARE complex from functioning normally to move TRPV1 to the cell membrane. A botulinum toxin A based molecule—BiTox—has been synthesized that is reported to retain neuronal silencing capacity without causing paralysis. This molecule reduces plasma extravasation and inflammatory edema but is not transported to the DRG ganglia or dorsal horn and does not inhibit pain behaviors in response to formalin or capsaicin and does not inhibit formalin-induced c-Fos expression in the dorsal horn. It was found to strongly reduce A-nociceptor mediated secondary mechanical hyperalgesia due to CFA joint inflammation or capsaicin injection and decreased hypersensitivity from nerve injury. The authors concluded that this botulinum toxin based molecule could reduce local release of neuromodulators from C fibers without impairing C nociceptive signaling function [37].

Vanilloids such as capsaicin (the active ingredient in hot chili peppers) and resiniferatoxin (a product of the plant *Euphorbia resinifera*) were first notable for their ability to produce burning pain when administered topically. Later, both molecules were found to have analgesic potential and subsequent work identified the non-selective cation channel to which these compounds bind. This receptor was found to be located on the dorsal root and trigeminal ganglia of various species. Subsequent work identified the channel, allowed cloning and cDNA characterization, and revealed that the channel could be activated not only by vanilloids but also by heat suggesting a role in thermosensation. The receptor was named transient receptor potential vanilloid 1 (TRPV1) and other ligands were identified making it a

Because of the variety of ligands, TRPV1 was considered a likely target for analgesia. Agonists such as vanilloids were noted to cause desensitization of these channels and in rodents as well as humans, pain behaviors could be alleviated with vanilloid treatment. TRPV1 knockout mice demonstrated reduced thermal hypersensitivity with inflammation. TRPV1 antagonists were shown to reverse pain behavior in rodents with a wide variety of painful conditions including inflammation, osteoarthritis and cancer. Both agonists and antagonists have been considered as analgesic therapies. Although systemic administration of vanilloids demonstrated analgesic efficacy in preclinical pain models, because of the undesirable systemic side effects of these compounds, most therapeutic trials have focused on local or topical administration of these compounds. Undesirable effects include hypotension, respiratory compromise and other negative effects on reflex pathways. Less pungent analogs were found to be less efficacious with respect to

**62**

analgesia [38].

#### **4.2 Vanilloids as analgesics—Human and pre-clinical studies**

In humans, current treatment of joint pain with vanilloids is limited to topical therapies. Pain relieving creams such as Zostrix® and patches such as Salonpas Hot Capsicum Patch® are available over the counter and contain capsaicin as the active ingredient. Multiple clinical trials have found modest benefit for osteoarthritis from low dose topical capsaicin [39–41]. More recently, a high dose 8% capsaicin patch has been approved for the treatment of post-herpetic neuralgia. According to the package insert, application of the patch requires careful adherence to application instructions by the health care professional and local anesthesia for the patient prior to application and systemic analgesics as needed in the post-application period. Interestingly, results from clinical trials of this drug for treatment of painful HIV neuropathy did not show clinical benefit [42, 43].

Resiniferatoxin (RTX) is an ultra-potent capsaicin (CAP) analogue [44], that is several thousand-fold more potent than CAP [45]. RTX in low concentrations produces a slow and sustained depolarization of membrane potential, preventing the generation of action potentials but causing less toxicity. A single IA injection in rats has been found to reduce hyperalgesia due to carrageenan induced joint pain [46].

RTX has been studied in clinical trials for other painful conditions. When given intravesicularly for interstitial cystitis and painful bladder syndrome, it did not improved overall symptoms of pain, urgency, frequency or nocturia [47, 48]. Adlea™ (4975) is another CAP analogue under development for the treatment of post-operative musculoskeletal pain, osteoarthritis and tendinopathy. Phase II trials of intra-articular injection of this compound were encouraging but no further clinical trials appear to have been performed [38]. Zucapsaicin (Civamide) is the cis-isomer of capsaicin, and functions as a TRPV1 blocker. Phase III trials have been done with topical civamide for OA knee pain [49]. This topical therapy is not absorbed systemically, is well tolerated, and produced significant improvement in Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical function score, pain score and subject global evaluation. Improvement was maintained for a year. This drug has not yet been approved by the US FDA.

#### **4.3 TRPV1 antagonists as analgesics**

**Arthritis model Experiment Results Reference** Rat carrageenaninduced acute joint pain IA RTX vs. vehicle given 24 hours after arthritis induction in a dose ranging study Significant reduction in pain behavior with RTX treatment [46] Rat MIA model early phase A-425619 given IP in a dose range during acute inflammatory phase 47% reduction in weightbearing asymmetry. Prolonged benefit [50, 51] Rat MIA model—late phase A-889425 and A-995662 given orally Reduced loss of grip force within 1 hour and maintained up to 8 hours [50, 52, 53] *IA—intra-articular, RTX—resiniferatoxin, MIA—monosodium iodoacetate.*

Several TRPV1 antagonists have also been identified that act as analgesics [50]. Some are more selective than others, complete nonselectivity producing inhibition of all modes of TRPV1 activation (protons, heat and capsaicin). More selectivity

#### **Table 2.**

*Preclinical studies of vanilloid agonists and antagonists as analgesics for arthritis pain.*

appears to improve the side effect profile. Centrally active TRPV1 antagonists appear to provide greater analgesia when given systemically or intrathecally in preclinical models of OA pain. Most preclinical studies of OA have been done in the monosodium iodoacetate (MIA) model in the rat (**Table 2**). Rats with MIA-induced arthritis pain demonstrate reduced weightbearing of the affected limb, pain with movement of the joint and hypersensitivity of uninjured tissues (secondary allodynia of the hind paw). These pain behaviors are thought to be due to both central and peripheral sensitization. TRPV1 antagonists appeared to be analgesic during both the acute inflammatory phase of MIA pain and later during the chronic phase [50–53]. Analgesia appears to improve with repeated dosing and side effects such as hyperthermia abate with some of the investigational TRPV1 antagonists. The potency of hyperthermia induction seems to relate most closely to the blockade of proton-induced TRPV1 activation [50].

Only a few TRPV1 antagonists have been used in clinical trials. ADZ1386 given orally in two different doses did not reduce OA pain more than placebo. A study in dogs with hip OA using oral ABT116 did not improve the total pain score, pain severity or pain interference score, but did reduce rescue medication use, increased night time activity levels and briefly produced an acute hyperthermic effect. NEO 6860, which is specific for blocking capsaicin activation of the target, with little or no effect against pH or heat activation, underwent a first-in-human phase I trial of the safety and efficacy of the drug in healthy human subjects [54]. The dose ranging study included 64 subjects and measured pharmacodynamics with a intradermal capsaicin test as well as pharmacokinetics. The drug was rapidly absorbed with a half-life of between 4 and 8 hours. Side effects included headache, paresthesia, nausea, and dizziness. Study participants were monitored specifically for increase in temperature and heat pain threshold/tolerance, but these were not noted. At all doses, most subjects reported a rapid onset, transient sensation of "feeling hot". The authors concluded that this compound had potential for development for treating OA-associated pain and future clinical studies were planned but have not yet been initiated.

#### **5. Other potentially analgesic neurotoxins**

#### **5.1 Conotoxin**

Ziconotide (ω-conopeptide MVIIA) is a synthetic compound of the neurotoxin ω-conopeptide derived from the Conus Magus fish hunting marine snail found in the Pacific Ocean. It selectively binds to the N-type voltage-gated calcium channels found in the laminae of the spinal cord's dorsal horn and blocks these channels. This blockade prevents calcium influx and halts neurotransmission thereby preventing nociceptive signaling. Pain transmission messages are prevented from arriving at the brain. It is FDA approved for intrathecal use for severe chronic pain in individuals who are intolerant of or refractory to other treatments including intrathecal (IT) morphine, but has demonstrated some serious side effects such as suicidal ideation and psychosis [55].

In a study of transgenic mice bred to express a membrane-tethered form of the conotoxin ω-conopeptide MVIIA under control of a nociceptor-specific gene, who were subjected to unilateral induction of joint inflammation with the antigen- and collagen- induced arthritis (ACIA) model, pain was effectively suppressed, but joint inflammation became persistent and more destructive. The authors concluded that blockade of CaV2.2-mediated calcium influx and nociceptive signaling by this toxin impaired recovery from induced inflammatory arthritis. They concluded that this

**65**

**7. Conclusions**

more specifically reduce pain perception.

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

blockade could lead to potentially deleterious and devastating effects if used during

Another neurotoxin studied as a potential analgesic is tetrodotoxin (TTX). Voltage-gated sodium channels (VGSCs) are critical for neuronal function and dysfunctional VGSCs have been implicated in several pain states. There are nine isoforms of the sodium channel alpha-subunit (Nav1.1–1.9 in mammals). Only Nav1.1–1.4 and Nav1.6–1.7 subtypes (TTX-sensitive channels) can be blocked by nanomolar concentrations of tetrodotoxin. Micromolar concentrations are required to block Nav1.5 and Nav1.8–1.9 subtypes (TTX-resistant channels) [56]. Although it appears to have little effect on acute pain further studies are needed. Analgesic efficacy in preclinical inflammatory pain models demonstrated promising effects of systemic administration for mechanical hyperalgesia and the neurogenic inflammatory response to injury. There are contradictory results for TTX efficacy for neuropathic pain. Effectiveness in preclinical models of neuropathic pain varied depending on dose, route of application, and appeared more effective in acute neural injury than in chronic neuropathic pain. In one clinical trial of tetrodotoxin for chemotherapy-induced neuropathic pain, injected TTX did not have a significant effect on pain [57]. There have been no specific studies evaluating tetrodotoxin for the treatment of chronic joint pain.

Thought not technically neurotoxins, several monoclonal antibodies have been developed against nerve growth factor (NGF) specifically for the treatment of chronic pain, and specifically for pain from OA. Tanezumab was the first of these to be developed. Three other companies have now created similar antibodies. Tanezumab was in phase III studies when the US FDA placed a hold on further clinical trials after an increase in joint destruction was observed in patients who had been given this drug. After that, preclinical studies suggested that this class of drugs could damage the autonomic nervous system, which delayed further research [58]. Since the hold was released in 2015, phase III clinical trials are being repeated. Results from those that have been published show that these biologic therapies appear to be effective with acceptable side effect profiles [59–61]. These therapies are administered parenterally, and therefore are systemically active. These antibodies have significant potential to improve analgesia for chronic arthritis pain.

Chronic joint pain is a significant public health problem that will only increase along with the aging population. In the absence of disease modifying treatments for OA, the need for better pain therapies will continue to increase. Neurotoxins can be helpful as adjunct treatments for pain, particularly in cases where peripheral sensitization has lowered pain thresholds and increased pain perception. Advances in understanding of the pathophysiologic mechanisms of nociception and sensitization and elucidation of the specific functions of the various neurotoxins will allow more advanced development of toxins that may avoid potential side effects and

Alternative routes of administration such as IA will be of interest.

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

**6. Anti-nerve growth factor**

inflammation [55].

**5.2 Tetrodotoxin**

blockade could lead to potentially deleterious and devastating effects if used during inflammation [55].

#### **5.2 Tetrodotoxin**

*From Conventional to Innovative Approaches for Pain Treatment*

proton-induced TRPV1 activation [50].

appears to improve the side effect profile. Centrally active TRPV1 antagonists appear to provide greater analgesia when given systemically or intrathecally in preclinical models of OA pain. Most preclinical studies of OA have been done in the monosodium iodoacetate (MIA) model in the rat (**Table 2**). Rats with MIA-induced arthritis pain demonstrate reduced weightbearing of the affected limb, pain with movement of the joint and hypersensitivity of uninjured tissues (secondary allodynia of the hind paw). These pain behaviors are thought to be due to both central and peripheral sensitization. TRPV1 antagonists appeared to be analgesic during both the acute inflammatory phase of MIA pain and later during the chronic phase [50–53]. Analgesia appears to improve with repeated dosing and side effects such as hyperthermia abate with some of the investigational TRPV1 antagonists. The potency of hyperthermia induction seems to relate most closely to the blockade of

Only a few TRPV1 antagonists have been used in clinical trials. ADZ1386 given orally in two different doses did not reduce OA pain more than placebo. A study in dogs with hip OA using oral ABT116 did not improve the total pain score, pain severity or pain interference score, but did reduce rescue medication use, increased night time activity levels and briefly produced an acute hyperthermic effect. NEO 6860, which is specific for blocking capsaicin activation of the target, with little or no effect against pH or heat activation, underwent a first-in-human phase I trial of the safety and efficacy of the drug in healthy human subjects [54]. The dose ranging study included 64 subjects and measured pharmacodynamics with a intradermal capsaicin test as well as pharmacokinetics. The drug was rapidly absorbed with a half-life of between 4 and 8 hours. Side effects included headache, paresthesia, nausea, and dizziness. Study participants were monitored specifically for increase in temperature and heat pain threshold/tolerance, but these were not noted. At all doses, most subjects reported a rapid onset, transient sensation of "feeling hot". The authors concluded that this compound had potential for development for treating OA-associated

pain and future clinical studies were planned but have not yet been initiated.

Ziconotide (ω-conopeptide MVIIA) is a synthetic compound of the neurotoxin ω-conopeptide derived from the Conus Magus fish hunting marine snail found in the Pacific Ocean. It selectively binds to the N-type voltage-gated calcium channels found in the laminae of the spinal cord's dorsal horn and blocks these channels. This blockade prevents calcium influx and halts neurotransmission thereby preventing nociceptive signaling. Pain transmission messages are prevented from arriving at the brain. It is FDA approved for intrathecal use for severe chronic pain in individuals who are intolerant of or refractory to other treatments including intrathecal (IT) morphine, but has demonstrated some serious side effects such as suicidal ideation

In a study of transgenic mice bred to express a membrane-tethered form of the conotoxin ω-conopeptide MVIIA under control of a nociceptor-specific gene, who were subjected to unilateral induction of joint inflammation with the antigen- and collagen- induced arthritis (ACIA) model, pain was effectively suppressed, but joint inflammation became persistent and more destructive. The authors concluded that blockade of CaV2.2-mediated calcium influx and nociceptive signaling by this toxin impaired recovery from induced inflammatory arthritis. They concluded that this

**5. Other potentially analgesic neurotoxins**

**64**

**5.1 Conotoxin**

and psychosis [55].

Another neurotoxin studied as a potential analgesic is tetrodotoxin (TTX). Voltage-gated sodium channels (VGSCs) are critical for neuronal function and dysfunctional VGSCs have been implicated in several pain states. There are nine isoforms of the sodium channel alpha-subunit (Nav1.1–1.9 in mammals). Only Nav1.1–1.4 and Nav1.6–1.7 subtypes (TTX-sensitive channels) can be blocked by nanomolar concentrations of tetrodotoxin. Micromolar concentrations are required to block Nav1.5 and Nav1.8–1.9 subtypes (TTX-resistant channels) [56]. Although it appears to have little effect on acute pain further studies are needed. Analgesic efficacy in preclinical inflammatory pain models demonstrated promising effects of systemic administration for mechanical hyperalgesia and the neurogenic inflammatory response to injury. There are contradictory results for TTX efficacy for neuropathic pain. Effectiveness in preclinical models of neuropathic pain varied depending on dose, route of application, and appeared more effective in acute neural injury than in chronic neuropathic pain. In one clinical trial of tetrodotoxin for chemotherapy-induced neuropathic pain, injected TTX did not have a significant effect on pain [57]. There have been no specific studies evaluating tetrodotoxin for the treatment of chronic joint pain.

### **6. Anti-nerve growth factor**

Thought not technically neurotoxins, several monoclonal antibodies have been developed against nerve growth factor (NGF) specifically for the treatment of chronic pain, and specifically for pain from OA. Tanezumab was the first of these to be developed. Three other companies have now created similar antibodies. Tanezumab was in phase III studies when the US FDA placed a hold on further clinical trials after an increase in joint destruction was observed in patients who had been given this drug. After that, preclinical studies suggested that this class of drugs could damage the autonomic nervous system, which delayed further research [58]. Since the hold was released in 2015, phase III clinical trials are being repeated. Results from those that have been published show that these biologic therapies appear to be effective with acceptable side effect profiles [59–61]. These therapies are administered parenterally, and therefore are systemically active. These antibodies have significant potential to improve analgesia for chronic arthritis pain. Alternative routes of administration such as IA will be of interest.

### **7. Conclusions**

Chronic joint pain is a significant public health problem that will only increase along with the aging population. In the absence of disease modifying treatments for OA, the need for better pain therapies will continue to increase. Neurotoxins can be helpful as adjunct treatments for pain, particularly in cases where peripheral sensitization has lowered pain thresholds and increased pain perception. Advances in understanding of the pathophysiologic mechanisms of nociception and sensitization and elucidation of the specific functions of the various neurotoxins will allow more advanced development of toxins that may avoid potential side effects and more specifically reduce pain perception.

### **Acknowledgements**

Thanks to Maren Mahowald who first introduced me to the concept of neurotoxins as therapy for joint pain.

### **Conflict of interest**

The author has no conflict of interest to declare.

### **Author details**

Hollis Krug Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota, USA

\*Address all correspondence to: hollis.krug@va.gov

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**67**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

cumulative update of research published through January 2009. Osteoarthritis and Cartilage. 2010;**18**(4):476-499

[9] Kirkley A, Birmingham TB, Litchfield RB, Giffin JR, Willits KR, Wong CJ, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. The New England Journal of Medicine. 2008;**359**(11):1097-1107

[10] Mosely JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, David H, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. The New England Journal of Medicine.

[11] Manchikanti L, Helm S 2nd, Fellows B, Janata JW, Pampati V, Grider JS, et al. Opioid epidemic in the United States. Pain Physician. 2012;**15**(3 Suppl):ES9-E38

[12] Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. Journal of the American Geriatrics Society.

[13] Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. Journal of the American Medical Association.

[14] Jevsevar D, Brown GA, Jones DL, Matzin EG, Manner P, Mooar P, et al. Treatment of Osteoarthritis of the Knee: Non-Arthroplasty Treatment. 2nd ed. Rosemont, IL: American Academy of

[15] Varacallo M, Johanson NA. Hip, replacement. In: Treasure Island. FL: StatPearls Publishing LLC; 2018

Orthopaedic Surgeons; 2013

2002;**347**:81-88

2013;**61**(3):335-340

2018;**319**(9):872-882

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

[1] Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated projected prevalence of self-reported doctor-diagnosed arthritis and arthritisattributable activity limitation among US adults, 2015-2040. Arthritis & Rhematology. 2016;**68**(7):1582-1587

[2] Hootman JM, Helmick

2006;**54**(1):226-229

2013;**9**(11):654-664

2013;**21**(9):1145-1153

1997;**56**(5):1397-1407

Ageing. 2013;**42**(3):272-278

CG. Projections of US prevalence of arthritis and associated activity limitations. Arthritis and Rheumatism.

[3] Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nature Reviews Rheumatology.

[4] Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis and Cartilage.

[5] Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Osteoarthritis and absenteeism costs: Evidence from US National survey data. Journal of Occupational and Environmental Medicine. 2010;**52**(3):263-268

[6] Yelin E, Murphy L, Cisternas M, Foreman A, Pasta D, Helmick C. Medical care expenditures and earnings losses among persons with arthritis and other rheumatic conditions in 2003, and comparisons to 1997. Arthritis and Rheumatism.

[7] Wenham CY, Conaghan PG. New horizons in osteoarthritis. Age and

[8] Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part III: Changes in evidence following systematic

**References**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain DOI: http://dx.doi.org/10.5772/intechopen.84593*

#### **References**

*From Conventional to Innovative Approaches for Pain Treatment*

The author has no conflict of interest to declare.

Thanks to Maren Mahowald who first introduced me to the concept of neuro-

**Acknowledgements**

**Conflict of interest**

toxins as therapy for joint pain.

**66**

**Author details**

Minnesota, USA

Hollis Krug

provided the original work is properly cited.

\*Address all correspondence to: hollis.krug@va.gov

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Minneapolis VA Health Care System, University of Minnesota, Minneapolis,

[1] Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated projected prevalence of self-reported doctor-diagnosed arthritis and arthritisattributable activity limitation among US adults, 2015-2040. Arthritis & Rhematology. 2016;**68**(7):1582-1587

[2] Hootman JM, Helmick CG. Projections of US prevalence of arthritis and associated activity limitations. Arthritis and Rheumatism. 2006;**54**(1):226-229

[3] Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nature Reviews Rheumatology. 2013;**9**(11):654-664

[4] Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis and Cartilage. 2013;**21**(9):1145-1153

[5] Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Osteoarthritis and absenteeism costs: Evidence from US National survey data. Journal of Occupational and Environmental Medicine. 2010;**52**(3):263-268

[6] Yelin E, Murphy L, Cisternas M, Foreman A, Pasta D, Helmick C. Medical care expenditures and earnings losses among persons with arthritis and other rheumatic conditions in 2003, and comparisons to 1997. Arthritis and Rheumatism. 1997;**56**(5):1397-1407

[7] Wenham CY, Conaghan PG. New horizons in osteoarthritis. Age and Ageing. 2013;**42**(3):272-278

[8] Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part III: Changes in evidence following systematic

cumulative update of research published through January 2009. Osteoarthritis and Cartilage. 2010;**18**(4):476-499

[9] Kirkley A, Birmingham TB, Litchfield RB, Giffin JR, Willits KR, Wong CJ, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. The New England Journal of Medicine. 2008;**359**(11):1097-1107

[10] Mosely JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, David H, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. The New England Journal of Medicine. 2002;**347**:81-88

[11] Manchikanti L, Helm S 2nd, Fellows B, Janata JW, Pampati V, Grider JS, et al. Opioid epidemic in the United States. Pain Physician. 2012;**15**(3 Suppl):ES9-E38

[12] Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. Journal of the American Geriatrics Society. 2013;**61**(3):335-340

[13] Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. Journal of the American Medical Association. 2018;**319**(9):872-882

[14] Jevsevar D, Brown GA, Jones DL, Matzin EG, Manner P, Mooar P, et al. Treatment of Osteoarthritis of the Knee: Non-Arthroplasty Treatment. 2nd ed. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2013

[15] Varacallo M, Johanson NA. Hip, replacement. In: Treasure Island. FL: StatPearls Publishing LLC; 2018

[16] Varacallo M, Johanson NA. Total knee arthoplasty. In: Treasure Island. FL: StatPearls Publishing LLC; 2018

[17] Feng JE, Novikov D, Anoushiravani AA, Schwarzkopf R. Total knee arthroplasty: Improving outcomes with a multidisciplinary approach. Journal of Multidisciplinary Healthcare. 2018;**11**:63-73

[18] Pavelka K. Treatment of pain in osteoarthritis. European Journal of Pain. 2000;**4**(Suppl A):23-30

[19] Dickenson A. The neurobiology of chronic pain states. Anaesthesia and Intensive Care Medicine. 2016;**17**(9):436-439

[20] Mahowald ML, Krug HE. Chronic musculoskeletal pain. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, editors. Kelly's Textbook of Rheumatology. I. 8th ed. Philadelphia, PA: Saunders Elsevier; 2009. pp. 963-992

[21] Montecucco C, Molgo J. Botulinal neurotoxins: Revival of an old killer. Current Opinion in Pharmacology. 2005;**5**(3):274-279

[22] Barash JR, Arnon SS. A novel strain of clostridium botulinum that produces type B and type H botulinum toxins. The Journal of Infectious Diseases. 2014;**209**(2):183-191

[23] Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotoxicity Research. 2006;**9**(2-3):179-188

[24] Wu T, Fu Y, Song HX, Ye Y, Dong Y, Li JH. Effectiveness of botulinum toxin for shoulder pain treatment: A systematic review and meta-analysis. Archives of Physical Medicine and Rehabilitation. 2015;**96**(12):2214-2220

[25] Wu T, Song HX, Dong Y, Ye Y, Li JH. Intra-articular injections of botulinum toxin a for refractory joint pain: A systematic review and meta-analysis. Clinical Rehabilitation. 2017;**31**(4):435-443

[26] Singh JA, Fitzgerald PM. Botulinum toxin for shoulder pain: A cochrane systematic review. The Journal of Rheumatology. 2011;**38**(3):409-418

[27] Kheniouia H, Houvenagel E, Catanzaritia JF, Guyota MA, Agnania O, Donzea C. Usefulness of intraarticular botulinum toxin injections. A systematic review. Joint, Bone, Spine. 2016;**83**:149-154

[28] Sun SF, Hsu CW, Lin HS, Chou YJ, Chen JY, Wang JL. Efficacy of intraarticular botulinum toxin A and intraarticular hyaluronate plus rehabilitation exercise in patients with unilateral ankle osteoarthritis: A randomized controlled trial. Journal of Foot and Ankle Research. 2014;**7**(1):9

[29] Sanders JO, Murray J, Gross L. Nonarthroplasty treatment of osteoarthritis of the knee. The Journal of the American Academy of Orthopaedic Surgeons. 2014;**22**(4):256-260

[30] Krug HE, Frizelle S, McGarraugh P, Mahowald ML. Pain behavior measures to quantitate joint pain and response to neurotoxin treatment in murine models of arthritis. Pain Medicine. 2009;**10**(7):1218-1228

[31] Blanshan N, Mahowald ML, Dorman C, Frizelle S, Krug HE. The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis. Toxicon. 2018;**158**:8-15

[32] Anderson S, Krug H, Dorman C, McGarraugh P, Frizelle S, Mahowald M. Analgesic effects of intra-articular

**69**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

capsaicin: A double-blind trial. Clinical Therapeutics. 1991;**13**(3):383-395

[41] McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. The Journal of Rheumatology.

[42] Brown S, Simpson DM, Moyle G, Brew BJ, Schifitto G, Larbalestier N, et al. NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory

polyneuropathy: Integrated analysis of two phase III, randomized, controlled trials. AIDS Research and Therapy.

[43] Clifford DB, Simpson DM, Brown S, Moyle G, Brew BJ, Conway B, et al. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. Journal of Acquired Immune Deficiency Syndromes.

[44] Rosenbaum T, Simon SA. TRPV1 receptors and signal transduction. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Frontiers in Neuroscience. Boca Raton, FL: CRC Press/Taylor &

[45] Szolcsanyi J, Szallasi A, Szallasi Z, Joo F, Blumberg PM. Resiniferatoxin: An ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons. The Journal of Pharmacology

[40] Kosuwon W, Sirichatiwapee W, Wisanuyotin T, Jeeravipoolvarn P, Laupattarakasem W. Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. Journal of the Medical Association of Thailand.

2010;**93**(10):1188-1195

1992;**19**(4):604-607

2013;**10**(1):5

2012;**59**(2):126-133

Francis; 2007

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

botulinum toxin type B in a murine model of chronic degenerative knee arthritis pain. Journal of Pain Research.

[33] Heikkila HM, Hielm-Bjorkman AK, Morelius M, Larsen S, Honkavaara

[34] Heikkila HM, Jokinen TS, Syrja P, Junnila J, Hielm-Bjorkman A, Laitinen-Vapaavuori O. Assessing adverse effects of intra-articular botulinum toxin A in healthy beagle dogs: A placebocontrolled, blinded, randomized trial. PLoS One. 2018;**13**(1):e0191043

[35] Lora VR, Clemente-Napimoga JT, Abdalla HB, Macedo CG, Canales GT, Barbosa CM. Botulinum toxin type A reduces inflammatory

hypernociception induced by arthritis in the temporomadibular joint of rats.

[36] Fan C, Chu X, Wang L, Shi H, Li T. Botulinum toxin type A reduces TRPV1 expression in the dorsal root ganglion in rats with adjuvant-arthritis

pain. Toxicon. 2017;**133**:116-122

[37] Mangione AS, Obara I, Maiaru M, Geranton SM, Tassorelli C, Ferrari E, et al. Nonparalytic botulinum molecules for the control of pain. Pain.

[38] Wong GY, Gavva NR. Therapeutic

[39] Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, et al. Treatment of arthritis with topical

potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Research Reviews.

Toxicon. 2017;**129**:52-57

2016;**157**(5):1045-1055

2009;**60**(1):267-277

J, Innes JF, et al. Intra-articular botulinum toxin A for the treatment of osteoarthritic joint pain in dogs: A randomized, double-blinded, placebocontrolled clinical trial. Veterinary Journal. 2014;**200**(1):162-169

2010;**3**:161-168

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain DOI: http://dx.doi.org/10.5772/intechopen.84593*

botulinum toxin type B in a murine model of chronic degenerative knee arthritis pain. Journal of Pain Research. 2010;**3**:161-168

*From Conventional to Innovative Approaches for Pain Treatment*

[25] Wu T, Song HX, Dong Y, Ye Y, Li JH. Intra-articular injections of botulinum toxin a for refractory joint pain: A systematic review and meta-analysis. Clinical Rehabilitation.

[26] Singh JA, Fitzgerald PM. Botulinum toxin for shoulder pain: A cochrane systematic review. The Journal of Rheumatology. 2011;**38**(3):409-418

[27] Kheniouia H, Houvenagel E, Catanzaritia JF, Guyota MA, Agnania O, Donzea C. Usefulness of intraarticular botulinum toxin injections. A systematic review. Joint, Bone, Spine.

[28] Sun SF, Hsu CW, Lin HS, Chou YJ, Chen JY, Wang JL. Efficacy of intraarticular botulinum toxin A and intraarticular hyaluronate plus rehabilitation exercise in patients with unilateral ankle osteoarthritis: A randomized controlled trial. Journal of Foot and Ankle Research. 2014;**7**(1):9

[29] Sanders JO, Murray J, Gross L. Nonarthroplasty treatment of osteoarthritis

[30] Krug HE, Frizelle S, McGarraugh P, Mahowald ML. Pain behavior measures to quantitate joint pain and response to neurotoxin treatment in murine models of arthritis. Pain Medicine.

of the knee. The Journal of the American Academy of Orthopaedic Surgeons. 2014;**22**(4):256-260

2009;**10**(7):1218-1228

Toxicon. 2018;**158**:8-15

[31] Blanshan N, Mahowald ML, Dorman C, Frizelle S, Krug HE. The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis.

[32] Anderson S, Krug H, Dorman C, McGarraugh P, Frizelle S, Mahowald M. Analgesic effects of intra-articular

2017;**31**(4):435-443

2016;**83**:149-154

[16] Varacallo M, Johanson NA. Total knee arthoplasty. In: Treasure Island. FL: StatPearls Publishing LLC; 2018

[17] Feng JE, Novikov D, Anoushiravani

AA, Schwarzkopf R. Total knee arthroplasty: Improving outcomes with a multidisciplinary approach. Journal of Multidisciplinary Healthcare.

[18] Pavelka K. Treatment of pain in osteoarthritis. European Journal of Pain.

[19] Dickenson A. The neurobiology of chronic pain states. Anaesthesia and Intensive Care Medicine.

[20] Mahowald ML, Krug HE. Chronic musculoskeletal pain. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, editors. Kelly's Textbook of Rheumatology. I. 8th ed. Philadelphia, PA: Saunders Elsevier;

[21] Montecucco C, Molgo J. Botulinal neurotoxins: Revival of an old killer. Current Opinion in Pharmacology.

[22] Barash JR, Arnon SS. A novel strain of clostridium botulinum that produces type B and type H botulinum toxins. The Journal of Infectious Diseases.

[23] Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotoxicity Research.

2018;**11**:63-73

2000;**4**(Suppl A):23-30

2016;**17**(9):436-439

2009. pp. 963-992

2005;**5**(3):274-279

2014;**209**(2):183-191

2006;**9**(2-3):179-188

[24] Wu T, Fu Y, Song HX, Ye Y, Dong Y, Li JH. Effectiveness of botulinum toxin for shoulder pain treatment: A systematic review and meta-analysis. Archives of Physical Medicine and Rehabilitation. 2015;**96**(12):2214-2220

**68**

[33] Heikkila HM, Hielm-Bjorkman AK, Morelius M, Larsen S, Honkavaara J, Innes JF, et al. Intra-articular botulinum toxin A for the treatment of osteoarthritic joint pain in dogs: A randomized, double-blinded, placebocontrolled clinical trial. Veterinary Journal. 2014;**200**(1):162-169

[34] Heikkila HM, Jokinen TS, Syrja P, Junnila J, Hielm-Bjorkman A, Laitinen-Vapaavuori O. Assessing adverse effects of intra-articular botulinum toxin A in healthy beagle dogs: A placebocontrolled, blinded, randomized trial. PLoS One. 2018;**13**(1):e0191043

[35] Lora VR, Clemente-Napimoga JT, Abdalla HB, Macedo CG, Canales GT, Barbosa CM. Botulinum toxin type A reduces inflammatory hypernociception induced by arthritis in the temporomadibular joint of rats. Toxicon. 2017;**129**:52-57

[36] Fan C, Chu X, Wang L, Shi H, Li T. Botulinum toxin type A reduces TRPV1 expression in the dorsal root ganglion in rats with adjuvant-arthritis pain. Toxicon. 2017;**133**:116-122

[37] Mangione AS, Obara I, Maiaru M, Geranton SM, Tassorelli C, Ferrari E, et al. Nonparalytic botulinum molecules for the control of pain. Pain. 2016;**157**(5):1045-1055

[38] Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Research Reviews. 2009;**60**(1):267-277

[39] Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, et al. Treatment of arthritis with topical capsaicin: A double-blind trial. Clinical Therapeutics. 1991;**13**(3):383-395

[40] Kosuwon W, Sirichatiwapee W, Wisanuyotin T, Jeeravipoolvarn P, Laupattarakasem W. Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. Journal of the Medical Association of Thailand. 2010;**93**(10):1188-1195

[41] McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. The Journal of Rheumatology. 1992;**19**(4):604-607

[42] Brown S, Simpson DM, Moyle G, Brew BJ, Schifitto G, Larbalestier N, et al. NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: Integrated analysis of two phase III, randomized, controlled trials. AIDS Research and Therapy. 2013;**10**(1):5

[43] Clifford DB, Simpson DM, Brown S, Moyle G, Brew BJ, Conway B, et al. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. Journal of Acquired Immune Deficiency Syndromes. 2012;**59**(2):126-133

[44] Rosenbaum T, Simon SA. TRPV1 receptors and signal transduction. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Frontiers in Neuroscience. Boca Raton, FL: CRC Press/Taylor & Francis; 2007

[45] Szolcsanyi J, Szallasi A, Szallasi Z, Joo F, Blumberg PM. Resiniferatoxin: An ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons. The Journal of Pharmacology and Experimental Therapeutics. 1990;**255**(2):923-928

[46] Kissin EY, Freitas CF, Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesthesia and Analgesia. 2005;**101**(5):1433-1439

[47] Chen TY, Corcos J, Camel M, Ponsot Y, Tu le M. Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC). International Urogynecology Journal and Pelvic Floor Dysfunction. 2005;**16**(4):293-297

[48] Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: A randomized, double-blind, placebo controlled trial. The Journal of Urology. 2005;**173**(5):1590-1594

[49] Schnitzer TJ, Pelletier JP, Haselwood DM, Ellison WT, Ervin JE, Gordon RD, et al. Civamide cream 0.075% in patients with osteoarthritis of the knee: A 12-week randomized controlled clinical trial with a longterm extension. The Journal of Rheumatology. 2012;**39**(3):610-620

[50] Kelly S. TRPV1 antagonists in the treatment of osteoarthritis pain. International Journal of Clinical Rheumatology. 2015;**10**(3):161-175

[51] Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, et al. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain. 2009;**142**(1-2):27-35

[52] Chu KL, Chandran P, Joshi SK, Jarvis MF, Kym PR, McGaraughty S. TRPV1-related modulation of spinal neuronal activity and behavior in a

rat model of osteoarthritic pain. Brain Research. 2011;**1369**:158-166

[53] Puttfarcken PS, Han P, Joshi SK, Neelands TR, Gauvin DM, Baker SJ, et al. A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl)phenyl) oxazol-2-ylamino)-1,2,3,4-tetrahydr onaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model. Pain. 2010;**150**(2):319-326

[54] Brown W, Leff RL, Griffin A, Hossack S, Aubray R, Walker P, et al. Safety, pharmacokinetics, and pharmacodynamics study in healthy subjects of oral NEO6860, a modality selective transient receptor potential vanilloid subtype 1 antagonist. The Journal of Pain. 2017;**18**(6):726-738

[55] Brookes ME, Eldabe S, Batterham A. Ziconotide monotherapy: A systematic review of randomised controlled trials. Current Neuropharmacology. 2017;**15**(2):217-231

[56] Nieto FR, Cobos EJ, Tejada MA, Sanchez-Fernandez C, Gonzalez-Cano R, Cendan CM. Tetrodotoxin (TTX) as a therapeutic agent for pain. Marine Drugs. 2012;**10**(2):281-305

[57] Kavoosi M. The Purpose of this Study Is to Determine if Tetrodotoxin (TTX) Is Effective in the Treatment of Pain Resulting from Chemotherapy Treatment (TTX-CINP-201). Bethesda, MD: U.S. National Library of Medicine; 2012. Available from: https:// clinicaltrials.gov/ct2/show/results/NCT 01655823?term=tetrodotoxin&rank=2 [Accessed: June 1, 2019]

[58] Mullard A. Drug developers reboot anti-NGF pain programmes. Nature Reviews. Drug Discovery. 2015;**14**(5):297-298

[59] Mayorga AJ, Wang S, Kelly KM, Thipphawong J. Efficacy and safety of

**71**

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84593*

fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: A randomised, placebo- and activecontrolled trial. International Journal of Clinical Practice. 2016;**70**(6):493-505

[60] Tiseo PJ, Kivitz AJ, Ervin JE, Ren H, Mellis SJ. Fasinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: Results from a double-blind, placebo-controlled exploratory study in osteoarthritis of the knee. Pain. 2014;**155**(7):1245-1252

[61] Ekman EF, Gimbel JS, Bello AE, Smith MD, Keller DS, Annis KM, et al. Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. The Journal of Rheumatology.

2014;**41**(11):2249-2259

*The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain DOI: http://dx.doi.org/10.5772/intechopen.84593*

fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: A randomised, placebo- and activecontrolled trial. International Journal of Clinical Practice. 2016;**70**(6):493-505

*From Conventional to Innovative Approaches for Pain Treatment*

rat model of osteoarthritic pain. Brain

[53] Puttfarcken PS, Han P, Joshi SK, Neelands TR, Gauvin DM, Baker SJ, et al. A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl)phenyl) oxazol-2-ylamino)-1,2,3,4-tetrahydr onaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model. Pain.

[54] Brown W, Leff RL, Griffin A, Hossack S, Aubray R, Walker P, et al. Safety, pharmacokinetics, and pharmacodynamics study in healthy subjects of oral NEO6860, a modality selective transient receptor potential vanilloid subtype 1 antagonist. The Journal of Pain. 2017;**18**(6):726-738

[55] Brookes ME, Eldabe S, Batterham A. Ziconotide monotherapy: A systematic review of randomised

Neuropharmacology. 2017;**15**(2):217-231

[56] Nieto FR, Cobos EJ, Tejada MA, Sanchez-Fernandez C, Gonzalez-Cano R, Cendan CM. Tetrodotoxin (TTX) as a therapeutic agent for pain. Marine

[57] Kavoosi M. The Purpose of this Study Is to Determine if Tetrodotoxin (TTX) Is Effective in the Treatment of Pain Resulting from Chemotherapy

Bethesda, MD: U.S. National Library of Medicine; 2012. Available from: https:// clinicaltrials.gov/ct2/show/results/NCT 01655823?term=tetrodotoxin&rank=2

controlled trials. Current

Drugs. 2012;**10**(2):281-305

Treatment (TTX-CINP-201).

[58] Mullard A. Drug developers reboot anti-NGF pain programmes. Nature Reviews. Drug Discovery.

[59] Mayorga AJ, Wang S, Kelly KM, Thipphawong J. Efficacy and safety of

[Accessed: June 1, 2019]

2015;**14**(5):297-298

Research. 2011;**1369**:158-166

2010;**150**(2):319-326

and Experimental Therapeutics.

[46] Kissin EY, Freitas CF, Kissin I. The effects of intraarticular resiniferatoxin

arthritis. Anesthesia and Analgesia.

[47] Chen TY, Corcos J, Camel M, Ponsot Y, Tu le M. Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial

Urogynecology Journal and Pelvic Floor Dysfunction. 2005;**16**(4):293-297

[48] Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: A randomized, double-blind, placebo controlled trial. The Journal of Urology.

[49] Schnitzer TJ, Pelletier JP, Haselwood DM, Ellison WT, Ervin JE, Gordon RD, et al. Civamide cream 0.075% in patients with osteoarthritis of the knee: A 12-week randomized controlled clinical trial with a longterm extension.

1990;**255**(2):923-928

in experimental knee-joint

cystitis (IC). International

2005;**173**(5):1590-1594

The Journal of Rheumatology.

[50] Kelly S. TRPV1 antagonists in the treatment of osteoarthritis pain. International Journal of Clinical Rheumatology. 2015;**10**(3):161-175

[51] Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, et al. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain.

[52] Chu KL, Chandran P, Joshi SK, Jarvis MF, Kym PR, McGaraughty S. TRPV1-related modulation of spinal neuronal activity and behavior in a

2012;**39**(3):610-620

2009;**142**(1-2):27-35

2005;**101**(5):1433-1439

**70**

[60] Tiseo PJ, Kivitz AJ, Ervin JE, Ren H, Mellis SJ. Fasinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: Results from a double-blind, placebo-controlled exploratory study in osteoarthritis of the knee. Pain. 2014;**155**(7):1245-1252

[61] Ekman EF, Gimbel JS, Bello AE, Smith MD, Keller DS, Annis KM, et al. Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. The Journal of Rheumatology. 2014;**41**(11):2249-2259

**73**

**Chapter 6**

**Abstract**

the treatment of pain.

musculoskeletal pain

**1. Introduction**

Features and Clinical Effectiveness

Musculoskeletal Pain Management

Pain is a symptom caused by a disease process and/or tissue injury. With the prolongation of life expectancy in humans, the incidence of degenerative joint diseases and as a result pain has increased. Unfortunately, a method of treatment that stops or reverses progression by affecting the pathogenesis in these diseases has not been developed. Physical therapeutics such as medicine and physical rehabilitation often are prescribed for patients suffering with pain. Recently, in addition to these routine therapies used in pain treatment, many regenerative injection-based therapies, including prolotherapy (PrT) or platelet-rich plasma (PRP) have been widely used. PrT is using for damaged or degenerated connective tissue healing, such as ligaments, tendons, and cartilage. The combination of local inflammatory effect, stimulation of local growth factor release, and down regulation of neuropathic inflammation can be defined as the mechanism. As a result of these, joint instability and ligament laxity reduce and pain decrease. PRP is the cellular component of the plasma. Although PRP is used for the same reasons as PrT, it can be used in acute cases unlike PrT. This chapter is intended to understand the use of regenerative injection therapies (PrT and PRP) better in

**Keywords:** regenerative injection treatments, prolotherapy, platelet-rich plasma,

prevention, early diagnosis, and the definite treatment method call has become the target of scientists. With the prolongation of life expectancy in humans, the incidence of degenerative joint diseases and as a result pain has increased. Unfortunately, a method of treatment that stops or reverses progression by affect-

Pain is a symptom caused by a disease process and/or tissue injury. Physical therapeutics, such as medicine and physical rehabilitation, often are prescribed for

ing the pathogenesis in these diseases has not been developed.

New developments are taking place every day in every field of medicine. Disease

of the Regenerative Injection

and Platelet-Rich Plasma for

Treatments: Prolotherapy

*Ilker Solmaz and Aydan Orscelik*

#### **Chapter 6**

## Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy and Platelet-Rich Plasma for Musculoskeletal Pain Management

*Ilker Solmaz and Aydan Orscelik*

### **Abstract**

Pain is a symptom caused by a disease process and/or tissue injury. With the prolongation of life expectancy in humans, the incidence of degenerative joint diseases and as a result pain has increased. Unfortunately, a method of treatment that stops or reverses progression by affecting the pathogenesis in these diseases has not been developed. Physical therapeutics such as medicine and physical rehabilitation often are prescribed for patients suffering with pain. Recently, in addition to these routine therapies used in pain treatment, many regenerative injection-based therapies, including prolotherapy (PrT) or platelet-rich plasma (PRP) have been widely used. PrT is using for damaged or degenerated connective tissue healing, such as ligaments, tendons, and cartilage. The combination of local inflammatory effect, stimulation of local growth factor release, and down regulation of neuropathic inflammation can be defined as the mechanism. As a result of these, joint instability and ligament laxity reduce and pain decrease. PRP is the cellular component of the plasma. Although PRP is used for the same reasons as PrT, it can be used in acute cases unlike PrT. This chapter is intended to understand the use of regenerative injection therapies (PrT and PRP) better in the treatment of pain.

**Keywords:** regenerative injection treatments, prolotherapy, platelet-rich plasma, musculoskeletal pain

#### **1. Introduction**

New developments are taking place every day in every field of medicine. Disease prevention, early diagnosis, and the definite treatment method call has become the target of scientists. With the prolongation of life expectancy in humans, the incidence of degenerative joint diseases and as a result pain has increased. Unfortunately, a method of treatment that stops or reverses progression by affecting the pathogenesis in these diseases has not been developed.

Pain is a symptom caused by a disease process and/or tissue injury. Physical therapeutics, such as medicine and physical rehabilitation, often are prescribed for patients suffering with pain [1]. Recently, in addition to these routine therapies used in pain treatment, many regenerative injection based-therapies, including prolotherapy (PrT) or platelet-rich plasma (PRP) have been widely used. The evidence for these treatments has arisen from the basic sciences and has been transformed into clinical research through controlled researches [2].

#### **2. Regenerative injection treatments**

#### **2.1 Prolotherapy**

PrT is derived from the words "proliferation" and "therapy" in Latin [3]. In the 1930s, it was introduced in the USA first, but the word "Prolotherapy" was first used by George Hackett in 1950. Dr. Hemwall's studies reported that 82% of the patients provided pain remission [4]. George Hackett formed the injection protocols for PrT in the 1950s depending on his clinical experience [4, 5]. Death of a case has been reported due to an allergic reaction due to phenol injection during PrT in 1959. After this negativity, this method has been removed to history [6].

PrT is an increasingly popular regenerative injection-based therapy and using for damaged or degenerated connective tissue healing, such as ligaments, tendons, and cartilage [7–10]. Following injury, chronic musculoskeletal pain develops if connective tissue repair is insufficient [4, 5]. Chronic musculoskeletal pain and disability often result from degeneration associated with these structures. PrT treatment can help us to correct this degeneration at the tissue level [4, 9]. We can correct this degeneration at the tissue level with the help of PrT. Pain reduction and regeneration mechanism are not clearly understood yet [7, 8]. However, the combination of local inflammatory effect, stimulation of local growth factor release, and down regulation of neuropathic inflammation can be defined as the mechanism [8, 11]. As a result of these, both joint instabilities with ligament laxity may reduce and also pain may reduce [12].

The proliferant solutions are used for injection into tender ligamentous and tendinous attachments and adjacent joint spaces. Irritants, osmotics, and chemotactics are proliferants commonly used in PrT. Irritants are phenol, guaiacol, and tannic acid. These damage cells. Particulates, that is, pumice flour, are also irritants but make cellular trauma and attract macrophages directly. Sodium morrhuate is a chemotactic and attract inflammatory cells. Glucose, glycerin, and zinc sulphate are the osmotic proliferants and cause osmotic shock to cells [12]. The most common injectant used in the randomized controlled trials (RCTs) is hypertonic dextrose [7, 11, 13]. Proliferant solutions may cause osmotic rupture of cells in the area in which they are applied and may direct to growth factor increase in various cells of human. Also, a hypertonic environment may lead to the release of DNA-encoding growth factors [11, 14]. Furthermore, various proliferant solutions cause fibroblast stimulation. Growth factors activate and also release the fibroblasts. The active fibroblasts secrete new collagen fibrils. Collagen fibrils are essential for the repair of damaged ligament and tendons and support healing [4, 10]. PrT tighten and strengthen the ligaments, tendons, and joint stabilizing structures. So, PrT could improve the stability of the joints [4, 10, 12, 15]. Increased joint stabilization could be associated with tissue healing process by increasing local blood flow and the excitability of mechanoreceptors and also by decreasing the excitability of pain receptors [4].

Instead of phenol, hypertonic dextrose solution can be done safely for PrT nowadays. The risk of side effects and complications is very low. As a result of this, hypertonic dextrose solutions with different concentrations (10–30%) have been

**75**

widely accepted.

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

commonly used in studies and books to date for PrT treatments. In these studies, greater than 10% of dextrose solutions proposed to use inflammatory response and proliferation. An animal study is designed for determining the optimal concentrations of dextrose solutions. This claimed that under the concentration of 10% only induce cell proliferation; however, do not have any effectivity on inflammation histology [16]. However, 5% dextrose solution increased gene expression in angiogenetic factors (platelet-derived growth factor (PDGF)-A and B, insulin-like growth factor-I, and vascular endothelial growth factor-A) and in apoptotic factors (caspase-3 and -8) in adult fibroblast culture [17]. High concentrations of glucose stimulate the PDGF activation. PDGF has two effects; first, it induces TGF-beta gene expression in mesangial cells, and second, it stimulates DNA synthesis [18]. Above the glucose concentrations of 10% make stimulus for the connective tissue growth factor and other genes expression in mesangial cells [19]. Cartilage volume stability improved by PrT injections, and this can be evaluated by magnetic reso-

Excessive pain and fatigue due to inflammatory reaction can occur after the PrT

PrT can be classified as enthesofascial, myofascial, and neurofascial according to

Enthesofascial/intra-articular PrT is the classic and traditional method of PrT. The injection location is on to the bony cortex/enthesis where the ligaments

Myofascial PrT is the other type of PrT. In this type, injection location is soft tissue of the bony cortex and below the subcutaneous fascia. This is used for degeneration of muscle and tendon, tears of muscle, defects of fascia. It prevents function

The neurofascial PrT is another type for PrT. Injection location is near to the peripheral sensory nerves and particularly their fascial penetrations. So this is performed to subcutaneous tissue. The goal of PrT is repairment or functional restoration of soft tissue, and neurofascial PrT produces the restoration of full function in small nerves. The reparative proteins and their correlation with nerve repairment are less well known. Nerves and ligament and tendon are covering with mainly collagen-based structure (i.e., perineurium). Nerves must take place in repair of soft tissue faults and that rather probably are planned to behave a similar order of growth factors. According to these reasons, dextrose is potentially therapeutic to small nerves [3]. However, this classification of neurofacial PrT is not

of muscle, or fascia surrounded by neovessels or neonerves.

injections. According to this rarely, treatment can be abandoned. To reduce the pain, hypertonic dextrose commonly combined with lidocaine, sensorcaine, and xylocaine as local anesthetics [20]. The local anesthetics delay and disrupt wound healing by inhibiting collagen synthesis in fibroblast tissue [21]. However, this

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

condition disrupts the outcome of the treatment.

*2.1.1.1 Enthesofascial/intra-articular PrT*

nance imaging [16].

*2.1.1 Classification*

injection location.

attach to or into joints.

*2.1.1.2 Myofascial PrT*

*2.1.1.3 The neurofascial PrT*

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

commonly used in studies and books to date for PrT treatments. In these studies, greater than 10% of dextrose solutions proposed to use inflammatory response and proliferation. An animal study is designed for determining the optimal concentrations of dextrose solutions. This claimed that under the concentration of 10% only induce cell proliferation; however, do not have any effectivity on inflammation histology [16]. However, 5% dextrose solution increased gene expression in angiogenetic factors (platelet-derived growth factor (PDGF)-A and B, insulin-like growth factor-I, and vascular endothelial growth factor-A) and in apoptotic factors (caspase-3 and -8) in adult fibroblast culture [17]. High concentrations of glucose stimulate the PDGF activation. PDGF has two effects; first, it induces TGF-beta gene expression in mesangial cells, and second, it stimulates DNA synthesis [18]. Above the glucose concentrations of 10% make stimulus for the connective tissue growth factor and other genes expression in mesangial cells [19]. Cartilage volume stability improved by PrT injections, and this can be evaluated by magnetic resonance imaging [16].

Excessive pain and fatigue due to inflammatory reaction can occur after the PrT injections. According to this rarely, treatment can be abandoned. To reduce the pain, hypertonic dextrose commonly combined with lidocaine, sensorcaine, and xylocaine as local anesthetics [20]. The local anesthetics delay and disrupt wound healing by inhibiting collagen synthesis in fibroblast tissue [21]. However, this condition disrupts the outcome of the treatment.

#### *2.1.1 Classification*

*From Conventional to Innovative Approaches for Pain Treatment*

into clinical research through controlled researches [2].

After this negativity, this method has been removed to history [6].

**2. Regenerative injection treatments**

**2.1 Prolotherapy**

and also pain may reduce [12].

decreasing the excitability of pain receptors [4].

patients suffering with pain [1]. Recently, in addition to these routine therapies used in pain treatment, many regenerative injection based-therapies, including prolotherapy (PrT) or platelet-rich plasma (PRP) have been widely used. The evidence for these treatments has arisen from the basic sciences and has been transformed

PrT is derived from the words "proliferation" and "therapy" in Latin [3]. In the 1930s, it was introduced in the USA first, but the word "Prolotherapy" was first used by George Hackett in 1950. Dr. Hemwall's studies reported that 82% of the patients provided pain remission [4]. George Hackett formed the injection protocols for PrT in the 1950s depending on his clinical experience [4, 5]. Death of a case has been reported due to an allergic reaction due to phenol injection during PrT in 1959.

PrT is an increasingly popular regenerative injection-based therapy and using for damaged or degenerated connective tissue healing, such as ligaments, tendons, and cartilage [7–10]. Following injury, chronic musculoskeletal pain develops if connective tissue repair is insufficient [4, 5]. Chronic musculoskeletal pain and disability often result from degeneration associated with these structures. PrT treatment can help us to correct this degeneration at the tissue level [4, 9]. We can correct this degeneration at the tissue level with the help of PrT. Pain reduction and regeneration mechanism are not clearly understood yet [7, 8]. However, the combination of local inflammatory effect, stimulation of local growth factor release, and down regulation of neuropathic inflammation can be defined as the mechanism [8, 11]. As a result of these, both joint instabilities with ligament laxity may reduce

The proliferant solutions are used for injection into tender ligamentous and tendinous attachments and adjacent joint spaces. Irritants, osmotics, and chemotactics are proliferants commonly used in PrT. Irritants are phenol, guaiacol, and tannic acid. These damage cells. Particulates, that is, pumice flour, are also irritants but make cellular trauma and attract macrophages directly. Sodium morrhuate is a chemotactic and attract inflammatory cells. Glucose, glycerin, and zinc sulphate are the osmotic proliferants and cause osmotic shock to cells [12]. The most common injectant used in the randomized controlled trials (RCTs) is hypertonic dextrose [7, 11, 13]. Proliferant solutions may cause osmotic rupture of cells in the area in which they are applied and may direct to growth factor increase in various cells of human. Also, a hypertonic environment may lead to the release of DNA-encoding growth factors [11, 14]. Furthermore, various proliferant solutions cause fibroblast stimulation. Growth factors activate and also release the fibroblasts. The active fibroblasts secrete new collagen fibrils. Collagen fibrils are essential for the repair of damaged ligament and tendons and support healing [4, 10]. PrT tighten and strengthen the ligaments, tendons, and joint stabilizing structures. So, PrT could improve the stability of the joints [4, 10, 12, 15]. Increased joint stabilization could be associated with tissue healing process by increasing local blood flow and the excitability of mechanoreceptors and also by

Instead of phenol, hypertonic dextrose solution can be done safely for PrT nowadays. The risk of side effects and complications is very low. As a result of this, hypertonic dextrose solutions with different concentrations (10–30%) have been

**74**

PrT can be classified as enthesofascial, myofascial, and neurofascial according to injection location.

#### *2.1.1.1 Enthesofascial/intra-articular PrT*

Enthesofascial/intra-articular PrT is the classic and traditional method of PrT. The injection location is on to the bony cortex/enthesis where the ligaments attach to or into joints.

#### *2.1.1.2 Myofascial PrT*

Myofascial PrT is the other type of PrT. In this type, injection location is soft tissue of the bony cortex and below the subcutaneous fascia. This is used for degeneration of muscle and tendon, tears of muscle, defects of fascia. It prevents function of muscle, or fascia surrounded by neovessels or neonerves.

#### *2.1.1.3 The neurofascial PrT*

The neurofascial PrT is another type for PrT. Injection location is near to the peripheral sensory nerves and particularly their fascial penetrations. So this is performed to subcutaneous tissue. The goal of PrT is repairment or functional restoration of soft tissue, and neurofascial PrT produces the restoration of full function in small nerves. The reparative proteins and their correlation with nerve repairment are less well known. Nerves and ligament and tendon are covering with mainly collagen-based structure (i.e., perineurium). Nerves must take place in repair of soft tissue faults and that rather probably are planned to behave a similar order of growth factors. According to these reasons, dextrose is potentially therapeutic to small nerves [3]. However, this classification of neurofacial PrT is not widely accepted.

#### *2.1.2 Indications and contraindications of PrT*

Indications of PrT are chronic musculoskeletal disorders such as chronic low back pain, osteoarthritis, epicondylitis, and rotator cuff lesions.

Contraindications of PrT are hereditary or acquired bleeding tendency, osteomyelitis, systemic infection, chronic infection history or active infection in the treatment region, rheumatic or other systemic inflammatory disease, oncological diseases, having been injected local corticosteroid within 12 weeks and allergy to the solution that is using for PrT.

#### *2.1.3 Disorders for PrT*

#### *2.1.3.1 Chronic low back pain*

Chronic low back pain is a common disease in the population. It causes temporary or permanent disability [12]. The results of the studies on this subject contain contradictions. Intra-articular PrT injection is significantly superior to corticosteroid injection in sacroiliac joint pain [22]. A RCT of sclerosing injections reported that PrT has similar result as saline plus lignocaine in chronic low back pain [23]. Injections performed once a week for 3 weeks unlike to normal use. Another RCT for nonspecific chronic low back pain compared PrT injections, saline injections, and exercises. All ligament injections caused meaningful decreases in pain and disability along the follow-up. Results are similar for PrT and saline or for exercises and daily life [24]. When integrated to spinal manipulation, exercise, and other interventions, PrT may have better impact on chronic low back pain and disability [12]. Also vitamin B12 usage increases the effectiveness of the treatment [25].

#### *2.1.3.2 Osteoarthritis*

Knee osteoarthritis is an important disease with increasing rate of pain, functional disability, and stiffness. A systematic review and meta-analysis compare the effect of dextrose PrT against control injections and exercise in the treatment of osteoarthritis. Dextrose PrT is superior to exercise, local anesthetics, and corticosteroids in 6 month follow-up [26]. Similar to this, a 3-arm, blinded, RCT compared dextrose PrT, saline, and at-home exercise, and PrT is better clinical enhance of pain, function, and stiffness than saline injections and at-home exercises [27]. There are more studies showing the success of PrT in knee osteoarthritis. Injection locations are different according to researchers; a combination of extra and intra-articular injection [28, 29], and only intra-articular [30, 31]. Combination of injections is thought to be an important treatment in young people with connective tissue disorders and also in elderly patients with severe knee osteoarthritis alternative to knee prosthesis. In these studies, it is reported that it not only reduced the pain but also corrected knee mechanical instability and cartilage damage.

Corticosteroid injections are an important treatment modality in symptomatic hand osteoarthritis [32]. The short-term effectiveness is well but the long-term effect is temporary. In carpometacarpal joint osteoarthritis, corticosteroid injection is superior to PrT at 1 month follow-up. Symptoms repeated with corticosteroid injection at the end of the sixth month, but improvement continued with PrT in the long-term and recurrence was less. PrT had better results in long term than corticosteroid injections [33].

**77**

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

Although PrT is a promising method for the treatment of epicondylitis, there are contradictions in a limited number of studies. In a randomized double-blind study PrT and placebo injections in patients with lateral epicondylitis compared PrT and placebo injections in patients with lateral epicondylitis. PrT was found to be significantly successful in pain and function [13]. A three-arm RCT reported PrT with dextrose and PrT with dextrose and sodium morrhuate were similar successful results for pain and function than wait and see group [7]. Subsequently, a double blinded RCT compared PrT and the corticosteroid injections, and no difference was

PrT injection to the shoulder region was first reported by Lee et al., and successful results have shown in patients with resistant to conservative treatment [34].

Adverse events change according to the localization of injections. Pain and stiffness may increase temporary, and these are the most common events. Also post-injection headache, postmenopausal spotting, pain with neurological features,

PRP is the cellular component of the plasma. It has a higher platelet concentration than whole blood [36]. Platelets are obtained by fragmentation of precursor megakaryocytes [37]. Activated platelets release clotting and growth factors in the α-granules. The main growth factors secreted by α-granules of platelets and effective in wound healing are known as PDGF, IGF-1, VEGF, TGF-β, and b-FGF [38]. Other factors such as serotonin, adenosine, dopamine, calcium, histamine, ADP, ATP, and catecholamine

Growth factors assure the release of other growth factors, enhancing healing process in chronic injuries and quickening repair in acute lesions [38–40]. It was first used to accelerate the wound healing of cutaneous ulcers in the 1980s [41]. The potential of regeneration and curative effect of PRP in oral implantology has been

Cellular components of plasma consist of 93% erythrocytes, 6% platelet, and 1% leukocytes. PRP contains platelets 3–5 times higher than whole blood. Depending

There is no accepted clear platelet concentration value for PRP. However, there are studies that report the healing effect when the number of platelets up to 150,000/

PRP is provided by centrifugation of autologous anticoagulant whole blood. Prior to centrifugation, citrate is added to whole blood for bounding ionized calcium and coagulation is prevented. After centrifugation, whole blood is divided into three layers according to gravity. The top layer consists of plasma, the middle layer called as "buffy coat" consists of platelets and leukocytes, and the lowest layer consists of erythrocytes [43]. A second centrifuge is applied to the buffy coat and plasma section, indicating

μl, and 350,000/μl in whole blood is above 1,000,000/μl in 5 ml plasma [42].

that PRP and platelet poor plasma may lead to further separation [44, 45].

in the dens granules of platelets also play a role in tissue regeneration [39].

demonstrated [42]. The usage of PRP has spread to other clinics [43].

on this, it contains growth factors in hyperphysiological rate [36].

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

found between groups in the same indication.

Similar results were obtained in RCT's [14, 35].

nausea, and diarrhea may occur, but transiently [12].

*2.1.3.3 Epicondylitis*

*2.1.3.4 Rotator cuff injuries*

*2.1.4 Adverse events*

**2.2 Platelet-rich plasma**

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

#### *2.1.3.3 Epicondylitis*

*From Conventional to Innovative Approaches for Pain Treatment*

back pain, osteoarthritis, epicondylitis, and rotator cuff lesions.

Indications of PrT are chronic musculoskeletal disorders such as chronic low

Contraindications of PrT are hereditary or acquired bleeding tendency, osteomyelitis, systemic infection, chronic infection history or active infection in the treatment region, rheumatic or other systemic inflammatory disease, oncological diseases, having been injected local corticosteroid within 12 weeks and allergy to

Chronic low back pain is a common disease in the population. It causes temporary or permanent disability [12]. The results of the studies on this subject contain contradictions. Intra-articular PrT injection is significantly superior to corticosteroid injection in sacroiliac joint pain [22]. A RCT of sclerosing injections reported that PrT has similar result as saline plus lignocaine in chronic low back pain [23]. Injections performed once a week for 3 weeks unlike to normal use. Another RCT for nonspecific chronic low back pain compared PrT injections, saline injections, and exercises. All ligament injections caused meaningful decreases in pain and disability along the follow-up. Results are similar for PrT and saline or for exercises and daily life [24]. When integrated to spinal manipulation, exercise, and other interventions, PrT may have better impact on chronic low back pain and disability [12]. Also vitamin B12 usage increases the effective-

Knee osteoarthritis is an important disease with increasing rate of pain, functional disability, and stiffness. A systematic review and meta-analysis compare the effect of dextrose PrT against control injections and exercise in the treatment of osteoarthritis. Dextrose PrT is superior to exercise, local anesthetics, and corticosteroids in 6 month follow-up [26]. Similar to this, a 3-arm, blinded, RCT compared dextrose PrT, saline, and at-home exercise, and PrT is better clinical enhance of pain, function, and stiffness than saline injections and at-home exercises [27]. There are more studies showing the success of PrT in knee osteoarthritis. Injection locations are different according to researchers; a combination of extra and intra-articular injection [28, 29], and only intra-articular [30, 31]. Combination of injections is thought to be an important treatment in young people with connective tissue disorders and also in elderly patients with severe knee osteoarthritis alternative to knee prosthesis. In these studies, it is reported that it not only reduced the pain but also corrected knee mechanical instability

Corticosteroid injections are an important treatment modality in symptomatic hand osteoarthritis [32]. The short-term effectiveness is well but the long-term effect is temporary. In carpometacarpal joint osteoarthritis, corticosteroid injection is superior to PrT at 1 month follow-up. Symptoms repeated with corticosteroid injection at the end of the sixth month, but improvement continued with PrT in the long-term and recurrence was less. PrT had better results in long term than cortico-

*2.1.2 Indications and contraindications of PrT*

the solution that is using for PrT.

*2.1.3 Disorders for PrT*

*2.1.3.1 Chronic low back pain*

ness of the treatment [25].

*2.1.3.2 Osteoarthritis*

and cartilage damage.

steroid injections [33].

**76**

Although PrT is a promising method for the treatment of epicondylitis, there are contradictions in a limited number of studies. In a randomized double-blind study PrT and placebo injections in patients with lateral epicondylitis compared PrT and placebo injections in patients with lateral epicondylitis. PrT was found to be significantly successful in pain and function [13]. A three-arm RCT reported PrT with dextrose and PrT with dextrose and sodium morrhuate were similar successful results for pain and function than wait and see group [7]. Subsequently, a double blinded RCT compared PrT and the corticosteroid injections, and no difference was found between groups in the same indication.

#### *2.1.3.4 Rotator cuff injuries*

PrT injection to the shoulder region was first reported by Lee et al., and successful results have shown in patients with resistant to conservative treatment [34]. Similar results were obtained in RCT's [14, 35].

#### *2.1.4 Adverse events*

Adverse events change according to the localization of injections. Pain and stiffness may increase temporary, and these are the most common events. Also post-injection headache, postmenopausal spotting, pain with neurological features, nausea, and diarrhea may occur, but transiently [12].

#### **2.2 Platelet-rich plasma**

PRP is the cellular component of the plasma. It has a higher platelet concentration than whole blood [36]. Platelets are obtained by fragmentation of precursor megakaryocytes [37]. Activated platelets release clotting and growth factors in the α-granules. The main growth factors secreted by α-granules of platelets and effective in wound healing are known as PDGF, IGF-1, VEGF, TGF-β, and b-FGF [38]. Other factors such as serotonin, adenosine, dopamine, calcium, histamine, ADP, ATP, and catecholamine in the dens granules of platelets also play a role in tissue regeneration [39].

Growth factors assure the release of other growth factors, enhancing healing process in chronic injuries and quickening repair in acute lesions [38–40]. It was first used to accelerate the wound healing of cutaneous ulcers in the 1980s [41]. The potential of regeneration and curative effect of PRP in oral implantology has been demonstrated [42]. The usage of PRP has spread to other clinics [43].

Cellular components of plasma consist of 93% erythrocytes, 6% platelet, and 1% leukocytes. PRP contains platelets 3–5 times higher than whole blood. Depending on this, it contains growth factors in hyperphysiological rate [36].

There is no accepted clear platelet concentration value for PRP. However, there are studies that report the healing effect when the number of platelets up to 150,000/ μl, and 350,000/μl in whole blood is above 1,000,000/μl in 5 ml plasma [42].

PRP is provided by centrifugation of autologous anticoagulant whole blood. Prior to centrifugation, citrate is added to whole blood for bounding ionized calcium and coagulation is prevented. After centrifugation, whole blood is divided into three layers according to gravity. The top layer consists of plasma, the middle layer called as "buffy coat" consists of platelets and leukocytes, and the lowest layer consists of erythrocytes [43]. A second centrifuge is applied to the buffy coat and plasma section, indicating that PRP and platelet poor plasma may lead to further separation [44, 45].

According to preparation technique and the resulting product ingredients, PRP is classified as: pure-PRP (P-PRP), leukocyte and leucocyte and PRP (L-PRP), and pure platelet-rich fibrin (P-PRF), leucocyte and platelet-rich fibrin (L-PRF). Nowadays, leukocytes can increase local inflammation, and leucocyte-poor content is shown to be superior to rich content. Centrifugation and activation methods are two important determinants of PRP quality and growth factor release. To date, there is no worldwide accepted PRP preparation protocol [45].

#### *2.2.1 Indications and contraindications of PRP*

Indications of PRP can be summarized as the acute/chronic musculoskeletal, cartilage and bone diseases such as chronic tendinopathies and enthesitis, acute/ chronic ligament injuries, acute/chronic muscle tears and strains, osteoarthritis, osteochondritis dissecans, arthroplasty operations, meniscus injuries, delayed fracture healing, nonunions, intervertebral disc injuries.

PRP's being an autologous graft minimizes the risk of allergic reaction and infectious disease. The side effects are pain formation due to local inflammatory response at the injection site, scar formation, and calcifications as infection and further possibilities at the rate of risk at all injections. Patient selection should be performed carefully as there is a risk of serious allergic reaction to bowel thrombin. The contraindications of PRP are the presence of tumors and metastatic disease, active infection, thrombocytopenia, anemia, pregnancy and lactation, and bowel thrombin allergy [46].

Acetaminophen and narcotic analgesics can be administered against pain, while nonsteroidal anti-inflammatory drugs are often banned for 2–4 weeks. It is thought that nonsteroidal anti-inflammatory drugs can inhibit the prostaglandin pathway and the beneficial effects of growth factors. Furthermore, in patients who received systemic steroids or immunosuppressive drugs, steroid injections were used instead of lesions in the last 6 weeks, and PRP injections were not preferred for NSAIDs in the last 7–10 days [36].

#### *2.2.2 Disorders for PRP*

#### *2.2.2.1 Rotator cuff injuries*

The recovery process in massive chronic rotator cuff tears often results with failure. PRP injection is not more effective than saline [47]. During the arthroscopic repair of full-thickness rotator cuff tears, PRP induces reduction in the pain level at the early postoperative period, a significant increase in shoulder function tests, and shoulder external rotation muscle strength in the short term; but there is no significant difference in pain, function, and MRI results in the long-term [48]. While PRP usage did not create a difference in arthroscopic repair of full-thickness rotator cuff tears, PRP was better for improvement in the arthroscopic repair of small and medium rotator cuff tears [49].

#### *2.2.2.2 Lateral epicondylitis*

The common feature of the lateral epicondylitis studies is the standardization of patient selection. PRP treatment is performed by the patients with chronic lateral epicondylitis who did not benefit from conservative treatment. Therefore, unlike to other disorders, standardization of the patient selection seems to be provided in the lateral epicondylitis.

PRP is superior to steroid injections for reducing pain and improving function [50–52]. Steroid injections have better results in the first weeks, deterioration occurs

**79**

**Figure 1.**

*Intra-articular PRP applications to the knee joint.*

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

Success of PRP was found more than 80% after 6 months of treatment [53].

especially after 26 weeks [50], and at the end of the second year, patients return to the baseline level [51]. PRP has a progressive improvement effect [50, 51], and this

In two studies conducted by the same author applying the same diagnosis and treatment, the total number of patients can be considered as 350. PRP by using the peppering technique is applied to extensor carpi radialis brevis tendon and vicinity.

Repeated injections are not superior to single dose administration in the treat-

PRP provides healing in pain and function even in patients with resistant patellar tendinopathy. Unlike the other injuries, 5 ml of PRP is injected into the tendon three times with an interval of 15 days [55, 56]. Even, ultrasound-guided PRP (by using peppering technique and ~2 ml/2 times/2 weeks intervals) was found to be superior

PRP injections were considered successful in the treatment of chronic refractory

Intra-articular PRP and hyaluronic acid provide similar clinical improvement. The success rate was higher in the joints with low degeneration at 6 and 12 month

While PRP treatment was shown to be significant in patellar and Achilles tendinopathy case series, it was similar as saline injection in RCTs. However, it is indicated that saline injection cannot be considered as placebo because of the

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

effect continues in the long term [51].

ment of chronic lateral epicondylitis [54].

*2.2.2.3 Patellar and Achilles tendinopathy*

Achilles tendinitis [59–61].

*2.2.2.4 Osteoarthritis*

from ESWT in the treatment of patellar tendinopathy [57].

mechanical effect caused by the needle and bleeding [58].

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

especially after 26 weeks [50], and at the end of the second year, patients return to the baseline level [51]. PRP has a progressive improvement effect [50, 51], and this effect continues in the long term [51].

In two studies conducted by the same author applying the same diagnosis and treatment, the total number of patients can be considered as 350. PRP by using the peppering technique is applied to extensor carpi radialis brevis tendon and vicinity. Success of PRP was found more than 80% after 6 months of treatment [53].

Repeated injections are not superior to single dose administration in the treatment of chronic lateral epicondylitis [54].

#### *2.2.2.3 Patellar and Achilles tendinopathy*

PRP provides healing in pain and function even in patients with resistant patellar tendinopathy. Unlike the other injuries, 5 ml of PRP is injected into the tendon three times with an interval of 15 days [55, 56]. Even, ultrasound-guided PRP (by using peppering technique and ~2 ml/2 times/2 weeks intervals) was found to be superior from ESWT in the treatment of patellar tendinopathy [57].

While PRP treatment was shown to be significant in patellar and Achilles tendinopathy case series, it was similar as saline injection in RCTs. However, it is indicated that saline injection cannot be considered as placebo because of the mechanical effect caused by the needle and bleeding [58].

PRP injections were considered successful in the treatment of chronic refractory Achilles tendinitis [59–61].

#### *2.2.2.4 Osteoarthritis*

*From Conventional to Innovative Approaches for Pain Treatment*

there is no worldwide accepted PRP preparation protocol [45].

fracture healing, nonunions, intervertebral disc injuries.

*2.2.1 Indications and contraindications of PRP*

the last 7–10 days [36].

*2.2.2 Disorders for PRP*

*2.2.2.1 Rotator cuff injuries*

medium rotator cuff tears [49].

*2.2.2.2 Lateral epicondylitis*

lateral epicondylitis.

According to preparation technique and the resulting product ingredients, PRP

Indications of PRP can be summarized as the acute/chronic musculoskeletal, cartilage and bone diseases such as chronic tendinopathies and enthesitis, acute/ chronic ligament injuries, acute/chronic muscle tears and strains, osteoarthritis, osteochondritis dissecans, arthroplasty operations, meniscus injuries, delayed

PRP's being an autologous graft minimizes the risk of allergic reaction and infectious disease. The side effects are pain formation due to local inflammatory response at the injection site, scar formation, and calcifications as infection and further possibilities at the rate of risk at all injections. Patient selection should be performed carefully as there is a risk of serious allergic reaction to bowel thrombin. The contraindications of PRP are the presence of tumors and metastatic disease, active infection, thrombocytopenia, anemia, pregnancy and lactation, and bowel thrombin allergy [46].

Acetaminophen and narcotic analgesics can be administered against pain, while nonsteroidal anti-inflammatory drugs are often banned for 2–4 weeks. It is thought that nonsteroidal anti-inflammatory drugs can inhibit the prostaglandin pathway and the beneficial effects of growth factors. Furthermore, in patients who received systemic steroids or immunosuppressive drugs, steroid injections were used instead of lesions in the last 6 weeks, and PRP injections were not preferred for NSAIDs in

The recovery process in massive chronic rotator cuff tears often results with failure. PRP injection is not more effective than saline [47]. During the arthroscopic repair of full-thickness rotator cuff tears, PRP induces reduction in the pain level at the early postoperative period, a significant increase in shoulder function tests, and shoulder external rotation muscle strength in the short term; but there is no significant difference in pain, function, and MRI results in the long-term [48]. While PRP usage did not create a difference in arthroscopic repair of full-thickness rotator cuff tears, PRP was better for improvement in the arthroscopic repair of small and

The common feature of the lateral epicondylitis studies is the standardization of patient selection. PRP treatment is performed by the patients with chronic lateral epicondylitis who did not benefit from conservative treatment. Therefore, unlike to other disorders, standardization of the patient selection seems to be provided in the

PRP is superior to steroid injections for reducing pain and improving function [50–52]. Steroid injections have better results in the first weeks, deterioration occurs

is classified as: pure-PRP (P-PRP), leukocyte and leucocyte and PRP (L-PRP), and pure platelet-rich fibrin (P-PRF), leucocyte and platelet-rich fibrin (L-PRF). Nowadays, leukocytes can increase local inflammation, and leucocyte-poor content is shown to be superior to rich content. Centrifugation and activation methods are two important determinants of PRP quality and growth factor release. To date,

**78**

Intra-articular PRP and hyaluronic acid provide similar clinical improvement. The success rate was higher in the joints with low degeneration at 6 and 12 month

**Figure 1.** *Intra-articular PRP applications to the knee joint.*


**Table 1.**

*Indications and contraindications of PrT and PRP applications.*

follow-up of PRP [62]. PRP is superior to placebo in the treatment of early stage knee osteoarthritis. Interestingly, a similar improvement is observed between single and two doses of PRP [63] (**Figure 1**).

Indications and contraindications of PrT and PRP applications are shown in **Table 1**.

#### **3. Conclusion**

It is obvious that increasing of the regenerative injection treatment types will continue progressively in the future. At the present time, PrT can be used as a simple, reliable, fast-acting treatment method in patients resistant to conservative treatment. Although PRP is used for the same diseases as PrT, it can also be used in acute cases unlike PrT. Both methods can be used with confidence in pain management. Proper patient selection is the most important issue to obtain effective results from methods.

#### **Declaration of conflicting interests**

The authors declared no conflicts of interest with respect to the authorship and/ or publication of this article.

#### **Funding**

The authors received no financial support for the research and/or authorship of this article.

**81**

**Author details**

Medicine, Ankara, Turkey

Ilker Solmaz1

provided the original work is properly cited.

\* and Aydan Orscelik<sup>2</sup>

Complementary Medicine Center, Ankara, Turkey

\*Address all correspondence to: ilkersolmaz72@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Health Sciences University Gulhane Education and Research Hospital

2 Health Sciences University Gulhane Medical Faculty, Department of Sports

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

### **Author details**

*From Conventional to Innovative Approaches for Pain Treatment*

Chronic low back pain, Osteoarthritis, Epicondylitis, Rotator cuff lesions.

cartilage and bone diseases; Chronic tendinopathies and

Acute/chronic ligament injuries, Acute/chronic muscle tears and

Osteoarthritis, Osteochondritis dissecans, Arthroplasty operations, Meniscus injuries, Delayed fracture healing,

Intervertebral disc injuries

*Indications and contraindications of PrT and PRP applications.*

PrT Chronic musculoskeletal disorders;

PRP Acute/chronic musculoskeletal,

enthesitis,

strains,

Nonunions,

**Application Indications Contraindications**

Hereditary or acquired bleeding tendency,

Chronic infection history or active infection in the treatment region, Rheumatic or other systemic

Having been injected local corticosteroid within 12 weeks, Allergy to the solution that is using for PrT.

Bowel thrombin allergy (if it is used as an activator)

Presence of tumors and metastatic disease, Active infection, Thrombocytopenia,

Osteomyelitis, Systemic infection,

Anemia,

inflammatory disease, Oncological diseases,

Pregnancy and lactation,

follow-up of PRP [62]. PRP is superior to placebo in the treatment of early stage knee osteoarthritis. Interestingly, a similar improvement is observed between single

Indications and contraindications of PrT and PRP applications are shown in **Table 1**.

It is obvious that increasing of the regenerative injection treatment types will continue progressively in the future. At the present time, PrT can be used as a simple, reliable, fast-acting treatment method in patients resistant to conservative treatment. Although PRP is used for the same diseases as PrT, it can also be used in acute cases unlike PrT. Both methods can be used with confidence in pain management. Proper patient selection is the most important issue to obtain effective results

The authors declared no conflicts of interest with respect to the authorship and/

The authors received no financial support for the research and/or authorship of

and two doses of PRP [63] (**Figure 1**).

**Declaration of conflicting interests**

or publication of this article.

**3. Conclusion**

**Table 1.**

from methods.

**Funding**

this article.

**80**

Ilker Solmaz1 \* and Aydan Orscelik<sup>2</sup>

1 Health Sciences University Gulhane Education and Research Hospital Complementary Medicine Center, Ankara, Turkey

2 Health Sciences University Gulhane Medical Faculty, Department of Sports Medicine, Ankara, Turkey

\*Address all correspondence to: ilkersolmaz72@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Adams ML, Arminio GJ. Nonpharmacologic pain management intervention. Clinics in Podiatric Medicine and Surgery. 2008;**25**(3):409-429. DOI: 10.1016/j.cpm.2008.02.003

[2] Sanapati J, Manchikanti L, Atluri S, Jordan S, Albers SL, Pappolla MA, et al. Do regenerative medicine therapies provide long-term relief in chronic low back pain: A systematic review and metaanalysis. Pain Physician. 2018;**21**(6):515-540

[3] Waldman SD. Pain Management. 2nd ed. Philadelphia: Saunders (Elsevier); 2011. 1027p

[4] Hackett GS, Hemwall GA, Montgomery GA. Ligaments and Tendon Relaxation Treated by Prolotherapy. 5th ed. USA: Hackett Hemwall Foundation; 2008

[5] Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clinical Journal of Sport Medicine. 2005;**15**:376

[6] Schneider RC, Williams JJ, Liss L. Fatality after injection of sclerosing agent to precipitate fibroosseous proliferation. Journal of the American Medical Association. 1959;**170**(15):1768-1772

[7] Rabago D, Lee KS, Ryan M, Chourasia AO, Sesto ME, Zgierska A, et al. Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): Results of a single-blind, pilot-level, randomized controlled trial. American Journal of Physical Medicine & Rehabilitation. 2013;**92**(7):587-596

[8] Louw F. The occasional prolotherapy for lateral epicondylosis (tennis elbow). Canadian Journal of Rural Medicine. 2014;**19**(1):31-33

[9] Chıldress MA, Beutler A. Management of chronic tendon injuries. American Family Physician. 2013;**87**(7):486-490

[10] Carayannopoulos A, Borg-Stein J, Sokolof J, Meleger A, Rosenberg D. Prolotherapy versus corticosteroid ınjections for the treatment of lateral epicondylosis a randomized controlled trial. PM & R : The Journal of Injury, Function, and Rehabilitation. 2011;**3**(8):706-715

[11] Yildiz Y, Apaydin AH, Seven MM, Orscelik A. The effects of prolotherapy (hypertonic dextrose) in recreational athletes with patellofemoral pain syndrome. Journal of Experimental and Integrative Medicine. 2016;**6**(2):53-56

[12] Dagenais S, Yelland MJ, Del Mar C, Schoene ML. Prolotherapy injections for chronic low-back pain. Cochrane Database of Systematic Reviews. 2007;**18**(2):CD004059

[13] Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell E. The efficacy of prolotherapy for lateral epicondylosis: A pilot study. Clinical Journal of Sport Medicine. 2008;**18**(3):248-254

[14] Seven MM, Ersen O, Akpancar S, Ozkan H, Turkkan S, Yıldız Y, et al. Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions. Orthopaedics & Traumatology, Surgery & Research. 2017;**103**(3):427-433. DOI: 10.1016/j. otsr.2017.01.003

[15] Linetsky FS, Rafael M, Saberski L. Pain management with regenerative injection therapy (RIT). In: Weiner RS, editor. Pain Management: A Practical Guide for Clinicians. Washington, DC: CRC Press; 2002. pp. 381-402

[16] Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Early

**83**

Inpress

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

Alternative and Complementary Medicine. 2010;**16**(12):1285-1290

[23] Dechow E, Davies RK, Carr AJ, Thompson PW. A randomized, doubleblind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology.

[24] Yelland M, Glasziou P, Bogduk N, Schluter P, McKernon M. Prolotherapy injections, saline injections, and exercises for chronic low back pain: A randomized trial. Spine.

1999;**38**:1255-1259

2004;**29**(1):9-16

[25] Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low-back pain. Cochrane Database of Systematic Reviews.

[26] Hung CY, Hsiao MY, Chang KV, Han DS, Wang TG. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: A systematic review and meta-analysis. Journal of Pain Research. 2016;**9**:847-

[27] Rabago D, Patterson J, Mundt M, Kijowski R, Grettie J, Segal N. Dextrose prolotherapy for knee osteoarthritis: A randomized controlled trial. Annals of Family Medicine. 2013;**11**:229-237

[28] Rabago D, Zgierska A, Fortney L, Kijowski R, Mundt M, Ryan M. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: Results of a single-arm uncontrolled study with 1-year follow-up. Journal of Alternative and Complementary

[29] Rezasoltani Z, Taheri M, Mofrad MK, Mohajerani SA. Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee

Medicine. 2012;**18**:408-414

2008;**16**(3):CD001824

857. eCollection 2016

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

ligaments to prolotherapy in a rat model. Journal of Orthopaedic Research. 2008;**26**(6):816-823. DOI: 10.1002/ jor.20600. [PubMed: 18240327]

inflammatory response of knee

[17] Guran S, Coban ZD, Karasimav O, et al. Dextrose solution used for prolotherapy decreases cell viability and increases gene expressions of angiogenic and apopitotic factors. Gulhane Medical

[18] Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. The American Journal of Pathology.

[19] Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. The Journal of Biological Chemistry.

[20] Akpancar S, Seven MM, Tuzun HY, Gurer L, Ekinci S. Current

concepts of prolotherapy in orthopedic surgery. Archives of Trauma Research. 2017;**6**(2):e40447. DOI: 10.5812/ atr.40447. DOI: 10.5812/atr.40447

[21] Drucker M, Cardenas E, Arizti P, Valenzuela A, Gamboa A. Experimental studies on the effect of lidocaine on wound healing. World Journal of Surgery. 1998;**22**(4):394-397. Discussion

397-398. PubMed PMID: 9523522

[22] Kim WM, Lee HG, Jeong CW, Kim CM, Yoon MH. A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. Journal of

Journal. 2018;**60**(2):42-46

1996;**149**(6):2095-2106

1999;**274**(9):5830-5834

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

inflammatory response of knee ligaments to prolotherapy in a rat model. Journal of Orthopaedic Research. 2008;**26**(6):816-823. DOI: 10.1002/ jor.20600. [PubMed: 18240327]

[17] Guran S, Coban ZD, Karasimav O, et al. Dextrose solution used for prolotherapy decreases cell viability and increases gene expressions of angiogenic and apopitotic factors. Gulhane Medical Journal. 2018;**60**(2):42-46

[18] Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. The American Journal of Pathology. 1996;**149**(6):2095-2106

[19] Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. The Journal of Biological Chemistry. 1999;**274**(9):5830-5834

[20] Akpancar S, Seven MM, Tuzun HY, Gurer L, Ekinci S. Current concepts of prolotherapy in orthopedic surgery. Archives of Trauma Research. 2017;**6**(2):e40447. DOI: 10.5812/ atr.40447. DOI: 10.5812/atr.40447 Inpress

[21] Drucker M, Cardenas E, Arizti P, Valenzuela A, Gamboa A. Experimental studies on the effect of lidocaine on wound healing. World Journal of Surgery. 1998;**22**(4):394-397. Discussion 397-398. PubMed PMID: 9523522

[22] Kim WM, Lee HG, Jeong CW, Kim CM, Yoon MH. A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. Journal of

Alternative and Complementary Medicine. 2010;**16**(12):1285-1290

[23] Dechow E, Davies RK, Carr AJ, Thompson PW. A randomized, doubleblind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology. 1999;**38**:1255-1259

[24] Yelland M, Glasziou P, Bogduk N, Schluter P, McKernon M. Prolotherapy injections, saline injections, and exercises for chronic low back pain: A randomized trial. Spine. 2004;**29**(1):9-16

[25] Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low-back pain. Cochrane Database of Systematic Reviews. 2008;**16**(3):CD001824

[26] Hung CY, Hsiao MY, Chang KV, Han DS, Wang TG. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: A systematic review and meta-analysis. Journal of Pain Research. 2016;**9**:847- 857. eCollection 2016

[27] Rabago D, Patterson J, Mundt M, Kijowski R, Grettie J, Segal N. Dextrose prolotherapy for knee osteoarthritis: A randomized controlled trial. Annals of Family Medicine. 2013;**11**:229-237

[28] Rabago D, Zgierska A, Fortney L, Kijowski R, Mundt M, Ryan M. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: Results of a single-arm uncontrolled study with 1-year follow-up. Journal of Alternative and Complementary Medicine. 2012;**18**:408-414

[29] Rezasoltani Z, Taheri M, Mofrad MK, Mohajerani SA. Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee

**82**

2014;**19**(1):31-33

*From Conventional to Innovative Approaches for Pain Treatment*

[9] Chıldress MA, Beutler A. Management of chronic tendon injuries. American Family Physician.

[10] Carayannopoulos A, Borg-Stein J, Sokolof J, Meleger A, Rosenberg D. Prolotherapy versus corticosteroid ınjections for the treatment of lateral epicondylosis a randomized controlled trial. PM & R : The Journal of Injury, Function, and Rehabilitation.

[11] Yildiz Y, Apaydin AH, Seven MM, Orscelik A. The effects of prolotherapy (hypertonic dextrose) in recreational athletes with patellofemoral pain syndrome. Journal of Experimental and Integrative Medicine. 2016;**6**(2):53-56

[12] Dagenais S, Yelland MJ, Del Mar C, Schoene ML. Prolotherapy injections for chronic low-back pain. Cochrane Database of Systematic Reviews.

[13] Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell E. The efficacy of prolotherapy for lateral epicondylosis: A pilot study. Clinical Journal of Sport

[14] Seven MM, Ersen O, Akpancar S, Ozkan H, Turkkan S, Yıldız Y, et al. Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions. Orthopaedics & Traumatology, Surgery & Research. 2017;**103**(3):427-433. DOI: 10.1016/j.

[15] Linetsky FS, Rafael M, Saberski L. Pain management with regenerative injection therapy (RIT). In: Weiner RS, editor. Pain Management: A Practical Guide for Clinicians. Washington, DC:

CRC Press; 2002. pp. 381-402

[16] Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Early

Medicine. 2008;**18**(3):248-254

2013;**87**(7):486-490

2011;**3**(8):706-715

2007;**18**(2):CD004059

otsr.2017.01.003

**References**

2018;**21**(6):515-540

2011. 1027p

[1] Adams ML, Arminio GJ. Nonpharmacologic pain management

and Surgery. 2008;**25**(3):409-429. DOI: 10.1016/j.cpm.2008.02.003

intervention. Clinics in Podiatric Medicine

[2] Sanapati J, Manchikanti L, Atluri S, Jordan S, Albers SL, Pappolla MA, et al. Do regenerative medicine therapies provide long-term relief in chronic low back pain: A systematic review and metaanalysis. Pain Physician.

[3] Waldman SD. Pain Management. 2nd ed. Philadelphia: Saunders (Elsevier);

[4] Hackett GS, Hemwall GA, Montgomery GA. Ligaments and Tendon Relaxation Treated by Prolotherapy. 5th ed. USA: Hackett

Hemwall Foundation; 2008

Sport Medicine. 2005;**15**:376

[6] Schneider RC, Williams JJ, Liss L. Fatality after injection of sclerosing agent to precipitate fibroosseous proliferation. Journal of the American Medical Association.

[7] Rabago D, Lee KS, Ryan M, Chourasia AO, Sesto ME, Zgierska A, et al. Hypertonic dextrose and morrhuate sodium injections

(prolotherapy) for lateral epicondylosis (tennis elbow): Results of a single-blind, pilot-level, randomized controlled trial. American Journal of Physical Medicine & Rehabilitation. 2013;**92**(7):587-596

[8] Louw F. The occasional prolotherapy for lateral epicondylosis (tennis elbow). Canadian Journal of Rural Medicine.

1959;**170**(15):1768-1772

[5] Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clinical Journal of osteoarthritis. Journal of Pain Research. 2017;**10**:1179-1187. DOI: 10.2147/JPR. S127633. eCollection 2017

[30] Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LL, Grasso R, et al. Chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PM & R : The Journal of Injury, Function, and Rehabilitation. 2016;**8**(11):1072-1082. DOI: 10.1016/j. pmrj.2016.03.008. Epub: April 4, 2016

[31] Reeves K, Hassanein K. Longterm effects of dextrose prolotherapy for anterior cruciate ligament laxity. Alternative Therapies in Health and Medicine. 2003;**9**:58-62

[32] Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly the Framingham study. American Journal of Epidemiology. 2002;**156**(11):1021-1027

[33] Jahangiri A, Moghaddam FR, Najafi S. Hypertonic dextrose versus corticosteroid local injection for the treatment of osteoarthritis in the first carpometacarpal joint: A double-blind randomized clinical trial. Journal of Orthopaedic Science. 2014;**19**(5):737-743

[34] Lee DH, Kwack KS, Rah UW, Yoon SH. Prolotherapy for refractory rotator cuff disease: Retrospective case-control study of 1-year follow-up. Archives of Physical Medicine and Rehabilitation. 2015;**96**(11):2027-2032

[35] Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng AL. Dextrose prolotherapy versus control injections in painful rotator cuff tendinopathy. Archives of Physical Medicine and Rehabilitation. 2016;**97**(1):17-25

[36] Nguyen RT, Borg-Stein J, McInnis K. Applications of platelet-rich plasma in musculoskeletal and sports medicine: An evidence-based approach. PM & R : The Journal of Injury, Function, and Rehabilitation. 2011;**3**(3):226-250

[37] Ahmad Z, Howard D, Brooks RA, Wardale J, Henson FMD, Getgood A, et al. The role of platelet rich plasma in musculoskeletal science. JRSM Short Reports. 2012;**3**(6):40

[38] Sanchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies in the treatment of orthopaedic sport injuries. Sports Medicine. 2009;**39**:345-354

[39] Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA. Plateletrich plasma: From basic science to clinical applications. The American Journal of Sports Medicine. 2009;**37**(11):2259-2272

[40] Marx RE. Platelet-rich plasma: Evidence to support its use. Journal of Oral and Maxillofacial Surgery. 2004;**62**:489-496

[41] Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care. 2001;**24**:483-488

[42] Marx RE. Platelet-rich plasma (PRP): What is PRP and what is not PRP? Implant Dentistry. 2001;**10**(4):225-228

[43] Anitua E, Sanchez M, Orive G, Andia I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials. 2007;**28**:4551-4560

[44] Mishra A, Woodall J, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clinics in Sports Medicine. 2009;**28**(1):113-125

[45] Jain A, Bedi RK, Mittal K. Plateletrich plasma therapy: A novel application in regenerative medicine.

**85**

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy…*

platelet rich plasma and corticosteroids

epicondylitis of humerus. Journal of Clinical and Diagnostic Research.

[53] Mishra AK, Skrepnik NV, Edwards SG, Jones GL, Sampson S, Vermillion DA, et al. Platelet-rich plasma

significantly improves clinical outcomes in patients with chronic tenis elbow. The American Journal of Sports Medicine.

[54] Glanzmann MC, Audige L. Platelet-

epicondylitis: Is one injection sufficient? Archives of Orthopaedic and Trauma Surgery. 2015;**135**(12):1637-1645

rich plasma for chronic lateral

[55] Kon E, Filardo G, Delcogliano M, Presti ML, Russo A, Bondi A, et al. Platelet-rich plasma: New clinical application: A pilot study for treatment of jumper's knee. Injury.

[56] Filardo G, Kon E, Della Villa S, Vincentelli F, Fornasari PM, Marcacci M. Use of platelet-rich plasma for the treatment of refractory jumper's knee. International Orthopaedics.

[57] Vetrano M, Castorina A, Vulpiani MC, Baldini R, Pavan A, Ferreti A. Platelet-rich plasma versus

focused shock waves in the treatment of jumper's knee in athletes. The American Journal of Sports Medicine.

[58] Di Matteo B, Filardo G, Kon E. Platelet-rich plasma: Evidence for the treatment of patellar and Achilles tendinopathy—A systematic review. Musculoskeletal Surgery. 2015;**99**:1-9

[59] Creaney L. Platelet-rich plasma for treatment of Achilles tendinopathy. JAMA. 2010;**303**(17):1696. Author reply:

in the treatment of lateral

2015;**9**(7):RC05-RC07

2014;**42**(2):463-471

2009;**40**(6):598-603

2010;**34**(6):909-915

2013;**41**(4):795-803

1697-1698

*DOI: http://dx.doi.org/10.5772/intechopen.84580*

Asian Journal of Transfusion Science.

[47] Kesikburun S, Tan AK, Yılmaz B, Yaşar E, Yazıcıoğlu K. Platelet-rich plasma injections in the treatment of chronic rotator cuff tendinopathy. The American Journal of Sports Medicine.

[48] Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. Journal of Shoulder and Elbow Surgery. 2011;**20**(4):518

[49] Cai YZ, Zhang C, Lin XJ. Efficacy of platelet-rich plasma in arthroscopic

[50] Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: Plateletrich plasma versus corticosteroid injection with a 1-year follow-up. The American Journal of Sports Medicine.

[51] Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: A double-blind randomized controlled trial with 2-year follow-up. The American Journal of Sports Medicine. 2011;**39**(6):1200-1208

[52] Yadav R, Kothari SY, Borah D. Comparison of local injection of

repair of full-thickness rotator cuff tears: A meta-analysis. Journal of Shoulder and Elbow Surgery.

2015;**24**(12):1852-1859

2010;**38**:255-262

[46] Sampson S, Gerhardt M, Mandelbaum B. Platelet rich plasma injection grafts for musculoskeletal injuries: A review. Current Reviews in Musculoskeletal Medicine.

2015;**9**(2):113-114

2008;**1**(3-4):165-174

2013;**41**(11):2609-2616

*Features and Clinical Effectiveness of the Regenerative Injection Treatments: Prolotherapy… DOI: http://dx.doi.org/10.5772/intechopen.84580*

Asian Journal of Transfusion Science. 2015;**9**(2):113-114

*From Conventional to Innovative Approaches for Pain Treatment*

in musculoskeletal and sports medicine: An evidence-based approach. PM & R : The Journal of Injury, Function, and Rehabilitation. 2011;**3**(3):226-250

[37] Ahmad Z, Howard D, Brooks RA, Wardale J, Henson FMD, Getgood A, et al. The role of platelet rich plasma in musculoskeletal science. JRSM Short

[38] Sanchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies

[39] Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA. Plateletrich plasma: From basic science to clinical applications. The American

in the treatment of orthopaedic sport injuries. Sports Medicine.

Journal of Sports Medicine. 2009;**37**(11):2259-2272

[40] Marx RE. Platelet-rich plasma: Evidence to support its use. Journal of Oral and Maxillofacial Surgery.

[41] Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care. 2001;**24**:483-488

[42] Marx RE. Platelet-rich plasma (PRP): What is PRP and what is not PRP? Implant Dentistry.

[43] Anitua E, Sanchez M, Orive G, Andia I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials. 2007;**28**:4551-4560

[44] Mishra A, Woodall J, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clinics in Sports Medicine. 2009;**28**(1):113-125

rich plasma therapy: A novel

[45] Jain A, Bedi RK, Mittal K. Platelet-

application in regenerative medicine.

Reports. 2012;**3**(6):40

2009;**39**:345-354

2004;**62**:489-496

2001;**10**(4):225-228

osteoarthritis. Journal of Pain Research. 2017;**10**:1179-1187. DOI: 10.2147/JPR.

[30] Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LL, Grasso R, et al. Chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee

osteoarthritis. PM & R : The Journal of Injury, Function, and Rehabilitation. 2016;**8**(11):1072-1082. DOI: 10.1016/j. pmrj.2016.03.008. Epub: April 4, 2016

[31] Reeves K, Hassanein K. Longterm effects of dextrose prolotherapy for anterior cruciate ligament laxity. Alternative Therapies in Health and

[32] Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly the Framingham study. American Journal of Epidemiology. 2002;**156**(11):1021-1027

[33] Jahangiri A, Moghaddam FR, Najafi S. Hypertonic dextrose versus corticosteroid local injection for the treatment of osteoarthritis in the first carpometacarpal joint: A double-blind randomized clinical trial. Journal of Orthopaedic Science.

[34] Lee DH, Kwack KS, Rah UW, Yoon SH. Prolotherapy for refractory rotator cuff disease: Retrospective case-control study of 1-year follow-up. Archives of Physical Medicine and Rehabilitation.

[35] Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng AL. Dextrose prolotherapy versus control injections in painful rotator cuff tendinopathy. Archives of Physical Medicine and Rehabilitation. 2016;**97**(1):17-25

[36] Nguyen RT, Borg-Stein J, McInnis K. Applications of platelet-rich plasma

2014;**19**(5):737-743

2015;**96**(11):2027-2032

Medicine. 2003;**9**:58-62

S127633. eCollection 2017

**84**

[46] Sampson S, Gerhardt M, Mandelbaum B. Platelet rich plasma injection grafts for musculoskeletal injuries: A review. Current Reviews in Musculoskeletal Medicine. 2008;**1**(3-4):165-174

[47] Kesikburun S, Tan AK, Yılmaz B, Yaşar E, Yazıcıoğlu K. Platelet-rich plasma injections in the treatment of chronic rotator cuff tendinopathy. The American Journal of Sports Medicine. 2013;**41**(11):2609-2616

[48] Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. Journal of Shoulder and Elbow Surgery. 2011;**20**(4):518

[49] Cai YZ, Zhang C, Lin XJ. Efficacy of platelet-rich plasma in arthroscopic repair of full-thickness rotator cuff tears: A meta-analysis. Journal of Shoulder and Elbow Surgery. 2015;**24**(12):1852-1859

[50] Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: Plateletrich plasma versus corticosteroid injection with a 1-year follow-up. The American Journal of Sports Medicine. 2010;**38**:255-262

[51] Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: A double-blind randomized controlled trial with 2-year follow-up. The American Journal of Sports Medicine. 2011;**39**(6):1200-1208

[52] Yadav R, Kothari SY, Borah D. Comparison of local injection of platelet rich plasma and corticosteroids in the treatment of lateral epicondylitis of humerus. Journal of Clinical and Diagnostic Research. 2015;**9**(7):RC05-RC07

[53] Mishra AK, Skrepnik NV, Edwards SG, Jones GL, Sampson S, Vermillion DA, et al. Platelet-rich plasma significantly improves clinical outcomes in patients with chronic tenis elbow. The American Journal of Sports Medicine. 2014;**42**(2):463-471

[54] Glanzmann MC, Audige L. Plateletrich plasma for chronic lateral epicondylitis: Is one injection sufficient? Archives of Orthopaedic and Trauma Surgery. 2015;**135**(12):1637-1645

[55] Kon E, Filardo G, Delcogliano M, Presti ML, Russo A, Bondi A, et al. Platelet-rich plasma: New clinical application: A pilot study for treatment of jumper's knee. Injury. 2009;**40**(6):598-603

[56] Filardo G, Kon E, Della Villa S, Vincentelli F, Fornasari PM, Marcacci M. Use of platelet-rich plasma for the treatment of refractory jumper's knee. International Orthopaedics. 2010;**34**(6):909-915

[57] Vetrano M, Castorina A, Vulpiani MC, Baldini R, Pavan A, Ferreti A. Platelet-rich plasma versus focused shock waves in the treatment of jumper's knee in athletes. The American Journal of Sports Medicine. 2013;**41**(4):795-803

[58] Di Matteo B, Filardo G, Kon E. Platelet-rich plasma: Evidence for the treatment of patellar and Achilles tendinopathy—A systematic review. Musculoskeletal Surgery. 2015;**99**:1-9

[59] Creaney L. Platelet-rich plasma for treatment of Achilles tendinopathy. JAMA. 2010;**303**(17):1696. Author reply: 1697-1698

[60] Paoloni J, de Vos RJ, Hamilton B, Murrell GA, Orchard J. Platelet-rich plasma treatment for ligament and tendon injuries. Clinical Journal of Sport Medicine. 2011;**21**(1):37-45

[61] Filardo G, Kon E, Di Matteo B, Di Martino A, Tesei G, Pelotti P, et al. Platelet-rich plasma injections for the treatment of refractory Achilles tendinopathy: Results at 4 years. Blood Transfusion. 2014;**12**(4):533-540

[62] Filardo G, Kon E, Di Matteo B, Merli ML, Cenacchi A, Fornasari PM, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: Study design and preliminary results of a randomized controlled trial. BMC Musculoskeletal Disorders. 2012;**13**:229

[63] Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: A prospective, double-blind, randomized trial. The American Journal of Sports Medicine. 2013;**41**(2):354-364

**87**

Section 3

Cancer Pain
