**3. Pain signal transmission**

To understand how to treat the pain from amputations, we should first take a moment to review how painful stimulation is transmitted through the body (see **Figure 1**). The human body receives signals from various inputs. If something painful happens to the body such as surgical insult, the damage is registered by nociceptors in the periphery. The distal nerve fibers coalesce and become peripheral nerves. There are pain receptors that present on the neuron and it is connected by an axon to the spinal cord. Transmission from peripheral nerve to dorsal column is obtained by different nerve fibers. These include: A-alpha fibers, the A-beta fibers, the A-delta fibers, and the C fibers. Pain travels on two different nerve fibers: A-delta and C-fibers. A-delta fibers are large myelinated fibers that carry sharp pain, whereas C-fibers are small and unmyelinated fibers that produce dull, slow spreading pain. This signal arrives to the dorsal horn and then travels up via neurotransmitters to the brain. There are a variety of neurotransmitters from the spinal cord to the thalamus. For pain, the most important to consider are Substance P which is an excitatory neurotransmitter for second order neurons in the dorsal horn. This neurotransmitter has been shown to sensitize nociceptors. In addition to pain, Substance P also related to inflammation, cell growth, vasodilation and even mood regulation. Glutamate is also a primary neurotransmitter for pain. It is the main excitatory neurotransmitter in the body. In the brain, glutamate receptors can be both pro-nociceptive as well as anti-nociceptive. This leads to many pain therapies constructed at glutamate. This is used for central sensitization in chronic pain patients [14]. Once in the dorsal horn, the second order neurons connect with thalamus and other various areas. These can include the somatosensory cortex (physical sensation), limbic system (emotion) and frontal cortex (upper level thinking). This allows a patient to feel and react with pain not just physically but emotionally as well [15].


**37**

may be experiencing.

*Amputation Pain Management*

*DOI: http://dx.doi.org/10.5772/intechopen.93846*

tion input, the phantom sensations occur [2, 9].

Let us revisit how the various pain pathways are affected during amputation. Phantom pain sensations likely result from changes in the somatosensory cortex. This causes afferent nociceptive stimulation from body parts near the amputation sites (such as face for upper extremity amputation or bladder for lower extremity amputation). Due to this reorganization in the somatosensory cortex and stimula-

Peripheral nerves likely play a large role in the phantom limb pain and residual limb pain. Damage to distal nerve endings and axons causes inflammation and alteration in neurotransmission along the usual pain pathway. The distal nerve endings will begin to regenerate but there will be non-functional axons, changes in sodium and potassium channels and different input from the spinal cord. Neuromas can form here as discussed previously. This can also result in higher pain due to more catecholamines in circulation due to increased sympathetic discharge [2, 9]. There are also spinal cord changes in the dorsal horn related to pain after amputation. The peripheral nerves are no longer able to send the usual signals along the axons to the spinal cord. The brainstem reticular areas therefore do not send inhibitory sensory transmission, so the dorsal horn receives input from this body

These changes in the peripheral and spinal cord need to be considered as we are

part as high sensory feedback resulting in pain transmission [1, 2, 9].

**4. Protocol for perioperative caring for amputation patients**

It is well understood that effective control of acute post-amputation pain results in decreased risk of development of residual and phantom limb pain [16]. Perioperative plans need to set up within a multi-disciplinary team, ideally involving surgeon, anesthesia, in-patient acute pain teams, pharmacy, physical therapy, occupational therapy, nutrition, and social work to name a few. The pre-operative optimization is essential to control of acute post-amputation pain and help decrease the risk of development of chronic and phantom pain to help these amputation patients have the best chance for better pain control post-amputation. Thorough pre-operative evaluation is needed to look at co-medical conditions that can be optimized. The patient's nutrition should be optimized for wound healing as well. Physical therapy and occupational therapy should work with the patient before surgery to improve physical status prior to surgery and make post-operative recovery more successful. Patient should have a pre-operative discussion about post-operative pain management and expectations. This will allow goal setting and help with anxiety the patient

Patients who struggle with high pain scores prior to amputation may have an elevated risk of developing chronic pain [17]. Thus, aggressive multimodal analgesic therapy instituted pre-operatively and early in the post-operative period could be beneficial in reducing the incidence of chronic pain. One study found that the presence of depressive symptoms was also a predictor of increased intensity of chronic pain in amputees [18]. Thus, it may be worthwhile to address these symptoms prior to elective amputation surgery. Patients with a complex history of chronic pain disorders and/or patients having high baseline daily opioid requirements (> 80 mg oral morphine equivalents) should be further selected to undergo a pre-operative appointment with a pain specialist. This appointment should ideally take place around 4 weeks prior to elective amputation with the goal to optimize the patient's pain regimen pre-operatively, by maximizing non-opioid modalities and reduction of daily opioid consumption if possible. This is done to improve response

thinking about treating each patient for amputation pain.

**Figure 1.** *Path pathways.*

#### *Amputation Pain Management DOI: http://dx.doi.org/10.5772/intechopen.93846*

*Pain Management - Practices, Novel Therapies and Bioactives*

To understand how to treat the pain from amputations, we should first take a moment to review how painful stimulation is transmitted through the body (see **Figure 1**). The human body receives signals from various inputs. If something painful happens to the body such as surgical insult, the damage is registered by nociceptors in the periphery. The distal nerve fibers coalesce and become peripheral nerves. There are pain receptors that present on the neuron and it is connected by an axon to the spinal cord. Transmission from peripheral nerve to dorsal column is obtained by different nerve fibers. These include: A-alpha fibers, the A-beta fibers, the A-delta fibers, and the C fibers. Pain travels on two different nerve fibers: A-delta and C-fibers. A-delta fibers are large myelinated fibers that carry sharp pain, whereas C-fibers are small and unmyelinated fibers that produce dull, slow spreading pain. This signal arrives to the dorsal horn and then travels up via neurotransmitters to the brain. There are a variety of neurotransmitters from the spinal cord to the thalamus. For pain, the most important to consider are Substance P which is an excitatory neurotransmitter for second order neurons in the dorsal horn. This neurotransmitter has been shown to sensitize nociceptors. In addition to pain, Substance P also related to inflammation, cell growth, vasodilation and even mood regulation. Glutamate is also a primary neurotransmitter for pain. It is the main excitatory neurotransmitter in the body. In the brain, glutamate receptors can be both pro-nociceptive as well as anti-nociceptive. This leads to many pain therapies constructed at glutamate. This is used for central sensitization in chronic pain patients [14]. Once in the dorsal horn, the second order neurons connect with thalamus and other various areas. These can include the somatosensory cortex (physical sensation), limbic system (emotion) and frontal cortex (upper level thinking). This allows a patient to feel and react with pain not just physically but

**3. Pain signal transmission**

emotionally as well [15].

**36**

**Figure 1.** *Path pathways.*

Let us revisit how the various pain pathways are affected during amputation. Phantom pain sensations likely result from changes in the somatosensory cortex. This causes afferent nociceptive stimulation from body parts near the amputation sites (such as face for upper extremity amputation or bladder for lower extremity amputation). Due to this reorganization in the somatosensory cortex and stimulation input, the phantom sensations occur [2, 9].

Peripheral nerves likely play a large role in the phantom limb pain and residual limb pain. Damage to distal nerve endings and axons causes inflammation and alteration in neurotransmission along the usual pain pathway. The distal nerve endings will begin to regenerate but there will be non-functional axons, changes in sodium and potassium channels and different input from the spinal cord. Neuromas can form here as discussed previously. This can also result in higher pain due to more catecholamines in circulation due to increased sympathetic discharge [2, 9].

There are also spinal cord changes in the dorsal horn related to pain after amputation. The peripheral nerves are no longer able to send the usual signals along the axons to the spinal cord. The brainstem reticular areas therefore do not send inhibitory sensory transmission, so the dorsal horn receives input from this body part as high sensory feedback resulting in pain transmission [1, 2, 9].

These changes in the peripheral and spinal cord need to be considered as we are thinking about treating each patient for amputation pain.

#### **4. Protocol for perioperative caring for amputation patients**

It is well understood that effective control of acute post-amputation pain results in decreased risk of development of residual and phantom limb pain [16]. Perioperative plans need to set up within a multi-disciplinary team, ideally involving surgeon, anesthesia, in-patient acute pain teams, pharmacy, physical therapy, occupational therapy, nutrition, and social work to name a few. The pre-operative optimization is essential to control of acute post-amputation pain and help decrease the risk of development of chronic and phantom pain to help these amputation patients have the best chance for better pain control post-amputation. Thorough pre-operative evaluation is needed to look at co-medical conditions that can be optimized. The patient's nutrition should be optimized for wound healing as well. Physical therapy and occupational therapy should work with the patient before surgery to improve physical status prior to surgery and make post-operative recovery more successful. Patient should have a pre-operative discussion about post-operative pain management and expectations. This will allow goal setting and help with anxiety the patient may be experiencing.

Patients who struggle with high pain scores prior to amputation may have an elevated risk of developing chronic pain [17]. Thus, aggressive multimodal analgesic therapy instituted pre-operatively and early in the post-operative period could be beneficial in reducing the incidence of chronic pain. One study found that the presence of depressive symptoms was also a predictor of increased intensity of chronic pain in amputees [18]. Thus, it may be worthwhile to address these symptoms prior to elective amputation surgery. Patients with a complex history of chronic pain disorders and/or patients having high baseline daily opioid requirements (> 80 mg oral morphine equivalents) should be further selected to undergo a pre-operative appointment with a pain specialist. This appointment should ideally take place around 4 weeks prior to elective amputation with the goal to optimize the patient's pain regimen pre-operatively, by maximizing non-opioid modalities and reduction of daily opioid consumption if possible. This is done to improve response

**Figure 2.**

*Protocol for amputation pain management.*

to opioid therapy in the immediate post-operative period. Thorough patient education and compassionate counseling also play a key role in developing a team relationship with the patient [19, 20]. See **Figure 2** for full protocol.

#### **5. Nerve blockade**

The current standard of care is pre-operative nerve blockade to prevent peripheral sensitization leading to future onset of phantom limb pain. Successful outcomes necessitate effective communication between the surgeon, anesthesiologist, and the various teams involved in the post-operative rehabilitation of the patient. A consultation with the Acute Pain Service or similar entity that performs peripheral nerve blockade pre-operatively and then follows the patient during their post-operative inpatient course is an important factor in the success in early prevention of acute and chronic pain for these patients.

Most patients that arrive for amputations should be evaluated to receive preoperative peripheral nerve blocks. If this cannot be done pre-operatively, patients can be evaluated post-operatively for a nerve block. If patients do not require post-operative anti-coagulation that will preclude a continuous peripheral nerve catheter, this would be the preferred nerve block for these patients as this will help with prevention phantom limb pain and chronic post-operative pain [3]. This can be utilized for 3–5 days. Continuous nerve catheter infusions have been found to decrease post-operative morphine requirements [21]. However, in addition, there are other factors that may preclude continuous peripheral nerve catheter placement such as infection, and patient factors. If this is the case, single shot peripheral nerve blocks may be utilized. Interestingly, a systematic review and meta-analysis found no difference in pain scores at 24 hours between patients that received a nerve block and those that did not [22]. However, this study did not look at chronic pain in these patients which is the important component that these nerve blocks are used for [9].

It is important to understand the anatomy of the amputation site to have successful nerve block placement. For example, a below the knee amputation will rely heavily on a sciatic nerve blockade whereas an above the knee amputation will need blockade of both femoral and sciatic nerves for successful pain control and help with peripheral sensitization for the patient [9]. For upper extremity amputations, a forearm

**39**

post op pain ratings [2, 3, 10].

**6.3 Gabapentinoids**

*Amputation Pain Management*

**6. Pharmacology**

**6.1 Opioids**

*DOI: http://dx.doi.org/10.5772/intechopen.93846*

amputation will be lower in the brachial plexus than an above the elbow amputation or shoulder disarticulation. Tourniquet site is also paramount when planning peripheral nerve block placement. If the catheter is in the surgical site or tourniquet site, there is a risk for dislodgement. It is important to remember this with placement and keep the securement of catheter out of the surgical field. This will take good commu-

It should be noted that epidural blockade may also be used for lower extremity amputation, especially if it will be a bilateral lower extremity amputation. There are studies that show pre-operative epidural placement in amputation patients prevent phantom limb pain due to stopping nociceptive input to the spinal cord [3]. There is no comparison of epidural to peripheral nerve catheters for lower extremity amputations, but on a practically note, peripheral nerve blockade will allow better mobilization and participation in physical therapy [3]. In addition, peripheral nerve block does not have the hemodynamic affects that epidural blockade can have [23].

Opioids remain a favored therapy for pain after surgery. They bind to Mu receptors in peripheral and central nerves as an agonist fashion to produce analgesia. They also can affect phantom limb pain by reducing cortical reorganization [10]. There is a wide variety to choose from post-operatively as they come in intravenous and oral formulation. Usually initially a parenteral opioid therapy with a patient-controlled analgesia (PCA) is started on post-operative day (POD) zero. Once the patient is tolerating a diet, the PCA is weaned down incrementally and oral opioid therapy is instituted. For opioid tolerant patients, we attempt to calculate their total daily morphine equivalent requirement and base our starting oral dose based on that. The goal is to wean off the PCA completely by 48 hours,

coinciding with the discontinuation of other intravenous infusion [10].

Ketamine has been studied for post-operative pain. It has been shown that the use of this medication lowers the opioid requirements and reverses opioid tolerance needed for acute post-operative pain [24]. Ketamine is a noncompetitive NMDA receptor antagonist that targets primarily in the brain and spinal cord. The NMDA receptor is important for synaptic plasticity, central sensitization, amplification of pain signals and opioid tolerance. For amputations, it lowers the dorsal horn sensitization and stops the events that may lead to phantom limb pain and residual limb pain. Important to note, it will not prevent phantom limb pain but will reduce risks of phantom limb pain and residual limb pain [9]. Ketamine has also been shown to have anti-inflammatory properties which may be effective in the early pre-operative phase. Ketamine infusions can be started in the operating room and continued for 2–3 days post-operatively. Studies show low does ketamine infusions do reduce opioids immediately post-op but there was not a significant reduction in immediate

Gabapentin and pregabalin are both anti-convulsant that inhibit alpha 2-delta

subunit of voltage-gated calcium channels. They are structural like GABA

**6.2 N-Methyl-D-Aspartate (NMDA) Receptor Antagonists**

nication between anesthesia provider and surgeon to achieve this effectively.

#### *Amputation Pain Management DOI: http://dx.doi.org/10.5772/intechopen.93846*

amputation will be lower in the brachial plexus than an above the elbow amputation or shoulder disarticulation. Tourniquet site is also paramount when planning peripheral nerve block placement. If the catheter is in the surgical site or tourniquet site, there is a risk for dislodgement. It is important to remember this with placement and keep the securement of catheter out of the surgical field. This will take good communication between anesthesia provider and surgeon to achieve this effectively.

It should be noted that epidural blockade may also be used for lower extremity amputation, especially if it will be a bilateral lower extremity amputation. There are studies that show pre-operative epidural placement in amputation patients prevent phantom limb pain due to stopping nociceptive input to the spinal cord [3]. There is no comparison of epidural to peripheral nerve catheters for lower extremity amputations, but on a practically note, peripheral nerve blockade will allow better mobilization and participation in physical therapy [3]. In addition, peripheral nerve block does not have the hemodynamic affects that epidural blockade can have [23].
