**1. Introduction**

#### **1.1 Chronic pain**

Pain occurs in all demographics, with a higher prevalence in some clusters (such as the elderly) and can be either acute or chronic [1, 2]. Chronic pain is a complex interplay between biology and psychology, where the intensity/magnitude differs depending on personal, sensory, emotional experience and persists more than 3 months beyond "normal" healing time [3, 4]. This type of pain affects more than 1.5 billion people worldwide [5] and has an estimated prevalence ranging between 17-27% [6–9]. Chronic pain represents a significant financial burden that exceeds

€300 trillion (approximately 1.5%-3% of the gross domestic product across the European Union) and up to \$635 billion in the United States [10, 11]. According to the International Association for the Study of Pain (IASP), the main overarching categories of chronic pain are primary (such as fibromyalgia) and secondary pain (the focus of this chapter). Secondary chronic pain is further divided into six distinct categories: cancer-related pain, postsurgical or posttraumatic pain, secondary headache/orofacial pain, secondary visceral pain, and secondary musculoskeletal pain [12, 13].

Most chronic pain begins with the occurrence of an acute injury event resulting in pain that if left untreated can develop chronically into a pathological condition and can increase the risk of future deleterious health issues such as sleep deficiency, delayed wound healing, immune dysfunction, cardiovascular problems (related to the stress response) and respiratory problems (such as pneumonia; [14, 15]). Persistent, unrelieved pain can negatively impact quality of life, daily functioning, sleep quality, work productivity and is associated with a substantial personal economic burden [16].

Pathologic pain is associated with multiple maladaptations in the nervous, endocrine, and immune systems [17–19] that often presents at multiple sites [20] and can be classified into nociceptive (somatic and visceral), neuropathic, nociplastic, or mixed [21]. Nociplastic describes pain of unknown origin that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors, evidence of disease or lesion of the somatosensory system causing the pain, such as early (pre structural damage) osteoarthritis [21]. Similarly, recent suggestions propose that generalised chronic pain is an expression of maladaptive plasticity within the nociceptive system [22, 23] and is relevant to the present chapter as osteoarthritic pain is generally accepted to be mainly of nociceptive origin [24].

#### **1.2 Mechanisms of nociceptive pain**

Most painful conditions initially involve the activation of dorsal root ganglion (DRG) neurons, which give rise to high threshold Aδ- and C-fibres (nociceptors) that innervate peripheral tissues (skin, bone, joints, viscera; [25]). Primary afferent neurons transduce painful stimuli action potentials through to the spinal cord (to ascending spinal neurons). Transmission of input from nociceptors, through the spinal column and to the central nerves system is mediated by monosynaptic contacts and/or through interneurons [19, 26]. In the spinal cord, neurotransmitter inhibition is mediated by the release of endogenous opioids (such as met-enkephalins and endorphins; [27]) or gamma-aminobutyric acid (GABA) which activate presynaptic opioid and/or GABA receptors on central nociceptor terminals to reduce excitatory transmitter release (**Figure 1**). The central integration of signals from excitatory and inhibitory neurotransmitters from cognitive, emotional, and environmental factors results in the perception of "pain". When the intricate balance between biological (neuronal), psychological (i.e. memory, distraction etc.) and social (i.e. attention, reward etc.) factors becomes disturbed, chronic pain develops [18].

Pain that is induced by an acute injury, initially localised, relatively proportional to the degree of tissue damage and typically increases with movement is referred to as "nociceptive pain." Specifically, as immune surveillance cells recognise the danger signals unmasked by tissue injury, the innate immune system initiates an inflammatory response to remove cellular debris and begins the healing process. Activated endothelial cells, stromal cells, and infiltrating immune cells release vasoactive and inflammatory mediators, including histamine, bradykinin, substance P, serotonin,

**163**

**Figure 1.**

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

nitric oxide, cytokines, chemokines, and prostaglandins, which amplify signal transduction in the peripheral terminals of nociceptors [26, 28]. These inflammatory mediators augment the responsiveness of nociceptors by increasing expression of pain-sensing ion channels and promoting release of pronociceptive mediators (autosensitization; [29]). This peripheral inflammation caused by local injury and continuous inputs from sensitised nociceptors promote 'central sensitization', a process that alters pain processing in the spinal dorsal horn, and in subcortical and cortical regions of the brain [30, 31]. Noxious signals associated with the injury are detected by peripheral nociceptor terminals of primary afferent neurons, transmitted via the spinal cord to the brain, processed and interpreted as highly unpleasant pain experiences [32]. Nociceptor terminals express molecules, such as transient receptor potential ion channels (TRP), voltage-gated sodium channels (Nav), voltage-gated calcium channels (VGCC), or acid-sensing ion channels (ASICs), which respond to heat, cold, acids, or mechanical stress and transduce them into action potentials [26]. The signal is then transmitted through peripheral axons to the cell bodies of the primary neurons, located in the dorsal root ganglia.

*Peripheral and central nociceptor pain signalling pathways following exposure to different pharmaceutical drugs. Without pharmaceutical intervention (naive state), activation of peripheral nociceptors in response to noxious stimuli, such as mechanical stress (OA) initiates the release of chemical mediators such as prostaglandins, bradykinin and cytokines at the peripheral terminal of the afferent neuron (peripheral* 

 *and K+*

*PLC releasing intracellular Ca2+ and the generation of action potential which transfers information to the (pre synapse) C-terminal afferent neuron (central sensitization). This triggers the release of neurotransmitters i.e. glutamate and substance P into the spinal synapse of the dorsal horn and activates AMPA or NMDA receptors* 

*influx and depolarization of the cell membrane. These signals travel to the brain where they are transcribed into the perception of pain. Pharmaceutical invention acts by modulating various aspects of the pain signalling pathway such as opioids (opioids such as morphine bind to GPCRs preventing the presynaptic release of a number of neurotransmitters), NSAIDs (inhibit the activity of COX) and acetaminophen (inhibits the activity of COX in the central nervous system but appears to lacks peripheral anti-inflammatory properties). Figure created using Biorender.com. Abbreviations: AMPAR,* α*-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; BK, bradykinin; COX, cyclooxygenase; GPCRs, G protein-coupled receptors; IL, interleukin; NMDAR, N-methyl-D-aspartate receptor; NAV, voltage-gated sodium channels; NGF, nerve growth factor; NF-*κ*B, nuclear factor kappa B; NSAID, nonsteroidal anti-inflammatory drug; PLC, phospholipase C; PKA, protein kinase a; PKC, protein kinase C; PGE, prostaglandin; P2X3, P2X purinoceptor 3 receptor; TNF, tumour necrosis factor; TRPV, transient receptor potential receptor.*

*on the post synaptic dorsal horn. As a result, there is an increased influx of Ca2+ and Na+*

 *channels. This results in the activation of PKA,* 

*, inhibition of K+*

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

*sensitisation) which is modulated by the GPCRs, NA<sup>+</sup>*

#### *Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.95919*

#### **Figure 1.**

*Pain Management - Practices, Novel Therapies and Bioactives*

pain [12, 13].

economic burden [16].

be mainly of nociceptive origin [24].

**1.2 Mechanisms of nociceptive pain**

€300 trillion (approximately 1.5%-3% of the gross domestic product across the European Union) and up to \$635 billion in the United States [10, 11]. According to the International Association for the Study of Pain (IASP), the main overarching categories of chronic pain are primary (such as fibromyalgia) and secondary pain (the focus of this chapter). Secondary chronic pain is further divided into six distinct categories: cancer-related pain, postsurgical or posttraumatic pain, secondary headache/orofacial pain, secondary visceral pain, and secondary musculoskeletal

Most chronic pain begins with the occurrence of an acute injury event resulting in pain that if left untreated can develop chronically into a pathological condition and can increase the risk of future deleterious health issues such as sleep deficiency, delayed wound healing, immune dysfunction, cardiovascular problems (related to the stress response) and respiratory problems (such as pneumonia; [14, 15]). Persistent, unrelieved pain can negatively impact quality of life, daily functioning, sleep quality, work productivity and is associated with a substantial personal

Pathologic pain is associated with multiple maladaptations in the nervous, endocrine, and immune systems [17–19] that often presents at multiple sites [20] and can be classified into nociceptive (somatic and visceral), neuropathic, nociplastic, or mixed [21]. Nociplastic describes pain of unknown origin that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors, evidence of disease or lesion of the somatosensory system causing the pain, such as early (pre structural damage) osteoarthritis [21]. Similarly, recent suggestions propose that generalised chronic pain is an expression of maladaptive plasticity within the nociceptive system [22, 23] and is relevant to the present chapter as osteoarthritic pain is generally accepted to

Most painful conditions initially involve the activation of dorsal root ganglion (DRG) neurons, which give rise to high threshold Aδ- and C-fibres (nociceptors) that innervate peripheral tissues (skin, bone, joints, viscera; [25]). Primary afferent neurons transduce painful stimuli action potentials through to the spinal cord (to ascending spinal neurons). Transmission of input from nociceptors, through the spinal column and to the central nerves system is mediated by monosynaptic contacts and/or through interneurons [19, 26]. In the spinal cord, neurotransmitter inhibition is mediated by the release of endogenous opioids (such as met-enkephalins and endorphins; [27]) or gamma-aminobutyric acid (GABA) which activate presynaptic opioid and/or GABA receptors on central nociceptor terminals to reduce excitatory transmitter release (**Figure 1**). The central integration of signals from excitatory and inhibitory neurotransmitters from cognitive, emotional, and environmental factors results in the perception of "pain". When the intricate balance between biological (neuronal), psychological (i.e. memory, distraction etc.) and social (i.e. attention, reward etc.) factors becomes disturbed, chronic pain

Pain that is induced by an acute injury, initially localised, relatively proportional to the degree of tissue damage and typically increases with movement is referred to as "nociceptive pain." Specifically, as immune surveillance cells recognise the danger signals unmasked by tissue injury, the innate immune system initiates an inflammatory response to remove cellular debris and begins the healing process. Activated endothelial cells, stromal cells, and infiltrating immune cells release vasoactive and inflammatory mediators, including histamine, bradykinin, substance P, serotonin,

**162**

develops [18].

*Peripheral and central nociceptor pain signalling pathways following exposure to different pharmaceutical drugs. Without pharmaceutical intervention (naive state), activation of peripheral nociceptors in response to noxious stimuli, such as mechanical stress (OA) initiates the release of chemical mediators such as prostaglandins, bradykinin and cytokines at the peripheral terminal of the afferent neuron (peripheral sensitisation) which is modulated by the GPCRs, NA<sup>+</sup> and K+ channels. This results in the activation of PKA, PLC releasing intracellular Ca2+ and the generation of action potential which transfers information to the (pre synapse) C-terminal afferent neuron (central sensitization). This triggers the release of neurotransmitters i.e. glutamate and substance P into the spinal synapse of the dorsal horn and activates AMPA or NMDA receptors on the post synaptic dorsal horn. As a result, there is an increased influx of Ca2+ and Na+ , inhibition of K+ influx and depolarization of the cell membrane. These signals travel to the brain where they are transcribed into the perception of pain. Pharmaceutical invention acts by modulating various aspects of the pain signalling pathway such as opioids (opioids such as morphine bind to GPCRs preventing the presynaptic release of a number of neurotransmitters), NSAIDs (inhibit the activity of COX) and acetaminophen (inhibits the activity of COX in the central nervous system but appears to lacks peripheral anti-inflammatory properties). Figure created using Biorender.com. Abbreviations: AMPAR,* α*-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; BK, bradykinin; COX, cyclooxygenase; GPCRs, G protein-coupled receptors; IL, interleukin; NMDAR, N-methyl-D-aspartate receptor; NAV, voltage-gated sodium channels; NGF, nerve growth factor; NF-*κ*B, nuclear factor kappa B; NSAID, nonsteroidal anti-inflammatory drug; PLC, phospholipase C; PKA, protein kinase a; PKC, protein kinase C; PGE, prostaglandin; P2X3, P2X purinoceptor 3 receptor; TNF, tumour necrosis factor; TRPV, transient receptor potential receptor.*

nitric oxide, cytokines, chemokines, and prostaglandins, which amplify signal transduction in the peripheral terminals of nociceptors [26, 28]. These inflammatory mediators augment the responsiveness of nociceptors by increasing expression of pain-sensing ion channels and promoting release of pronociceptive mediators (autosensitization; [29]). This peripheral inflammation caused by local injury and continuous inputs from sensitised nociceptors promote 'central sensitization', a process that alters pain processing in the spinal dorsal horn, and in subcortical and cortical regions of the brain [30, 31]. Noxious signals associated with the injury are detected by peripheral nociceptor terminals of primary afferent neurons, transmitted via the spinal cord to the brain, processed and interpreted as highly unpleasant pain experiences [32]. Nociceptor terminals express molecules, such as transient receptor potential ion channels (TRP), voltage-gated sodium channels (Nav), voltage-gated calcium channels (VGCC), or acid-sensing ion channels (ASICs), which respond to heat, cold, acids, or mechanical stress and transduce them into action potentials [26]. The signal is then transmitted through peripheral axons to the cell bodies of the primary neurons, located in the dorsal root ganglia.

Unmyelinated C-fibres and myelinated Aδ-fibres transmit noxious stimuli, whereas thinly myelinated Aδ-fibres transmit innocuous mechanical stimuli, such as touch. The central axons of the primary neurons enter the spinal cord through the dorsal horn and synapse with secondary somatosensory neurons and, to some extent, with motor neurons to form withdrawal reflex circuits. Signal propagation to the secondary neurons is subject to modulation by descending tracts from the brainstem and by interneurons in the dorsal horn. The signal is then transmitted to the thalamus, from where tertiary afferent neurons are projected to multiple areas of the cortex involved in pain processing [33].

## **1.3 Mechanisms of neuropathic pain**

Neuropathic pain (NP) is defined as "pain caused by a lesion or disease of the somatosensory nervous system" [34]. Chronic neuropathic pain is caused by damage to nerve fibres that respond by misappropriating sensory inputs leading to spontaneous painful sensation, through multiple mechanisms in the nervous system and its associated modulators. Peripheral nerve damage can result in chronic neuropathic pain through multiple routes [35] via peripheral pain-processing unmyelinated C-fibres and thinly-myelinated fibres because of metabolic damage, toxins, medications, cytokines, and inflammation [36]. This can result in morphological and chemical changes such as fibre density and neuronal hyperexcitability [30, 37–40]. Throughout the axon, trauma, compression, hypoxia, inflammation and chemical damage lead to fibre degeneration and alterations in gene expression [41], resulting in ectopic firing, faulty signal transmission [42], detrimental physiological alterations [43–45] and peripheral second-order targets [46–48]. This results in negative impacts on nociceptive pathways causing them to become sensitised [49], leading to maladaptive central sensitization [50] and increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input [51]. At the molecular level, these damaged processes disrupt second-order neuronal transduction, through alterations in receptor expression, calcium permeability, synapse location and the release of pain-promoting mediators [52–55]. The precise molecular targets of neuropathic pain stem from multiple mechanisms of peripheral nerve fibre excitation and sensitization leading to sustained electrochemical signalling and to neuropathic pain stimulus [56, 57].

#### **1.4 Pharmaceutical treatment of chronic pain**

Both acute and chronic pain are, in general, treated with a wide group of pharmaceutical medications known as "analgesics." The most frequently used are opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, also referred to as acetaminophen or N-acetyl-p-aminophenol [58].

#### *1.4.1 Opioids*

Opioid drugs (e.g. morphine, codeine, methadone, fentanyl and their derivatives) are the most widely used analgesic medications globally, so much so that an estimated 26.8 million people were living with 'opioid use disorder' globally in 2016, resulting in >100,000 opioid overdose deaths annually [59]. Opioids are a group of pharmaceutical formulations that interact with endogenous opioid receptors to distort neurotransmitter singling pathways through localised peripheral sensory neurons [60, 61] with the goal to reducing pain sensation. Opioid receptors are a large superfamily of seven-transmembrane G protein-coupled receptors and are classified as μ (μ1, μ2, μ3), δ (δ1, δ2), k (k1, k2, k3) and ORL1 [62, 63], of which

**165**

following references [83–86].

studies [75, 78, 87–89].

*1.4.2 Non-steroidal anti-inflammatory drugs (NSAIDs)*

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

almost all opioid drugs in use today interact with μ receptors. These receptors are inhibitory and prevent the presynaptic release of a number of neurotransmitters to inhibit the release of glutamate, calcitonin gene related protein (CGRP), and substance P. This is an important action considering the established roles of these molecules in pain signalling and nociceptive transmission (**Figure 1**; [64]). For example, morphine, extracted from opium, is by far the most commonly known opioid [59], which is thought to have been in use since the third century B.C. [22], but identified at the molecular level with high binding affinity to sites in the intestine and brain [65]. These receptors mediate an inhibitory signal of neural transmission induced by opioid drugs to produce an analgesic action (**Figure 1**). Pain stimuli are detected by nociceptors at the spinal cord dorsal horn [66] where they act on the substantia gelatinosa (inhibitory interneurons rich with opioid receptors) and are activated by the antinociceptive descending system, to control the transmission of painful stimuli from primary nerve fibres to spino-thalamic neurons [22]. Opioid receptors have an intricate relationship with inflammatory status. Early studies showed that the systemic or local application of receptor agonists elicited greater analgesic effects in inflamed compared to non-inflamed tissue (reviewed in; [67]). Furthermore, opioid receptor trafficking (movement within the neuron) is augmented, expression on DRG membranes is enhanced [68, 69] and axonal transport stimulated by cytokines and nerve growth factor that are produced within inflamed tissues [70, 71]. This enhanced/altered state resulted in increased

antinociceptive function of opioid receptors on peripheral nerves [60, 72].

The major limiting factors of opioid therapy are the variety of side effects such as constipation, vomiting, myosis, cough reflex suppression, modulation of the immune system and one of the most dangerous, respiratory rhythm and respiratory depression [73, 74]. Interestingly, studies have shown that long-term use in chronic non-malignant (e.g. musculoskeletal) pain has not been proven effective [75], rather, abuse of prescription opioids have reached epidemic proportions leading to addiction, overdoses and increased death rates [76–78]. Importantly, these side effects may be drug specific and affect immune function differently [79, 80]. Nonetheless, chronic use of opioid medication can cause cellular adaptions that lead to modulation of cellular growth, inflammation, wound healing [81, 82]. For a more detailed overview of the potential side effects and opioid tolerance refer to the

Regardless of the potential impact that opioid agonists could have on pain relief, meta-analyses show no improvement in clinically significant pain reduction scores, and epidemiological data suggest that quality of life and functional capacity are only minimally changed [75, 78]. Nonetheless, more data is required from larger studies (specifically in OA), however the aforementioned adverse effects and lack of analgesic efficacy has led to significant dropout rates in long-term

NSAIDs (particular enzyme inhibiters) are among the most widely used medications globally [90, 91] because of the lower potential for addiction (as shown by the US opioid epidemic; [92]), robust efficacy, and long history of clinical use [93].

The prevalence of 'non-aspirin' NSAID use has been well studied and is dynamic across age, body mass index and geographical ancestry, ranging between ~15-45%, women being the highest users and ibuprofen generally being the most reported [94–96]. Short-term use of NSAIDs is particularly prevalent (~50–80% per year) in athletes and soldiers (individuals that may be at risk for acute and chronic musculoskeletal injuries; [97–99]). Extended periods of NSAID treatment (e.g., more

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

#### *Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.95919*

*Pain Management - Practices, Novel Therapies and Bioactives*

involved in pain processing [33].

**1.3 Mechanisms of neuropathic pain**

**1.4 Pharmaceutical treatment of chronic pain**

Unmyelinated C-fibres and myelinated Aδ-fibres transmit noxious stimuli, whereas thinly myelinated Aδ-fibres transmit innocuous mechanical stimuli, such as touch. The central axons of the primary neurons enter the spinal cord through the dorsal horn and synapse with secondary somatosensory neurons and, to some extent, with motor neurons to form withdrawal reflex circuits. Signal propagation to the secondary neurons is subject to modulation by descending tracts from the brainstem and by interneurons in the dorsal horn. The signal is then transmitted to the thalamus, from where tertiary afferent neurons are projected to multiple areas of the cortex

Neuropathic pain (NP) is defined as "pain caused by a lesion or disease of the somatosensory nervous system" [34]. Chronic neuropathic pain is caused by damage to nerve fibres that respond by misappropriating sensory inputs leading to spontaneous painful sensation, through multiple mechanisms in the nervous system and its associated modulators. Peripheral nerve damage can result in chronic neuropathic pain through multiple routes [35] via peripheral pain-processing unmyelinated C-fibres and thinly-myelinated fibres because of metabolic damage, toxins, medications, cytokines, and inflammation [36]. This can result in morphological and chemical changes such as fibre density and neuronal hyperexcitability [30, 37–40]. Throughout the axon, trauma, compression, hypoxia, inflammation and chemical damage lead to fibre degeneration and alterations in gene expression [41], resulting in ectopic firing, faulty signal transmission [42], detrimental physiological alterations [43–45] and peripheral second-order targets [46–48]. This results in negative impacts on nociceptive pathways causing them to become sensitised [49], leading to maladaptive central sensitization [50] and increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input [51]. At the molecular level, these damaged processes disrupt second-order neuronal transduction, through alterations in receptor expression, calcium permeability, synapse location and the release of pain-promoting mediators [52–55]. The precise molecular targets of neuropathic pain stem from multiple mechanisms of peripheral nerve fibre excitation and sensitization leading to sustained electrochemical signalling and to neuropathic pain stimulus [56, 57].

Both acute and chronic pain are, in general, treated with a wide group of pharmaceutical medications known as "analgesics." The most frequently used are opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, also

Opioid drugs (e.g. morphine, codeine, methadone, fentanyl and their derivatives) are the most widely used analgesic medications globally, so much so that an estimated 26.8 million people were living with 'opioid use disorder' globally in 2016, resulting in >100,000 opioid overdose deaths annually [59]. Opioids are a group of pharmaceutical formulations that interact with endogenous opioid receptors to distort neurotransmitter singling pathways through localised peripheral sensory neurons [60, 61] with the goal to reducing pain sensation. Opioid receptors are a large superfamily of seven-transmembrane G protein-coupled receptors and are classified as μ (μ1, μ2, μ3), δ (δ1, δ2), k (k1, k2, k3) and ORL1 [62, 63], of which

referred to as acetaminophen or N-acetyl-p-aminophenol [58].

**164**

*1.4.1 Opioids*

almost all opioid drugs in use today interact with μ receptors. These receptors are inhibitory and prevent the presynaptic release of a number of neurotransmitters to inhibit the release of glutamate, calcitonin gene related protein (CGRP), and substance P. This is an important action considering the established roles of these molecules in pain signalling and nociceptive transmission (**Figure 1**; [64]). For example, morphine, extracted from opium, is by far the most commonly known opioid [59], which is thought to have been in use since the third century B.C. [22], but identified at the molecular level with high binding affinity to sites in the intestine and brain [65]. These receptors mediate an inhibitory signal of neural transmission induced by opioid drugs to produce an analgesic action (**Figure 1**). Pain stimuli are detected by nociceptors at the spinal cord dorsal horn [66] where they act on the substantia gelatinosa (inhibitory interneurons rich with opioid receptors) and are activated by the antinociceptive descending system, to control the transmission of painful stimuli from primary nerve fibres to spino-thalamic neurons [22]. Opioid receptors have an intricate relationship with inflammatory status. Early studies showed that the systemic or local application of receptor agonists elicited greater analgesic effects in inflamed compared to non-inflamed tissue (reviewed in; [67]). Furthermore, opioid receptor trafficking (movement within the neuron) is augmented, expression on DRG membranes is enhanced [68, 69] and axonal transport stimulated by cytokines and nerve growth factor that are produced within inflamed tissues [70, 71]. This enhanced/altered state resulted in increased antinociceptive function of opioid receptors on peripheral nerves [60, 72].

The major limiting factors of opioid therapy are the variety of side effects such as constipation, vomiting, myosis, cough reflex suppression, modulation of the immune system and one of the most dangerous, respiratory rhythm and respiratory depression [73, 74]. Interestingly, studies have shown that long-term use in chronic non-malignant (e.g. musculoskeletal) pain has not been proven effective [75], rather, abuse of prescription opioids have reached epidemic proportions leading to addiction, overdoses and increased death rates [76–78]. Importantly, these side effects may be drug specific and affect immune function differently [79, 80]. Nonetheless, chronic use of opioid medication can cause cellular adaptions that lead to modulation of cellular growth, inflammation, wound healing [81, 82]. For a more detailed overview of the potential side effects and opioid tolerance refer to the following references [83–86].

Regardless of the potential impact that opioid agonists could have on pain relief, meta-analyses show no improvement in clinically significant pain reduction scores, and epidemiological data suggest that quality of life and functional capacity are only minimally changed [75, 78]. Nonetheless, more data is required from larger studies (specifically in OA), however the aforementioned adverse effects and lack of analgesic efficacy has led to significant dropout rates in long-term studies [75, 78, 87–89].

#### *1.4.2 Non-steroidal anti-inflammatory drugs (NSAIDs)*

NSAIDs (particular enzyme inhibiters) are among the most widely used medications globally [90, 91] because of the lower potential for addiction (as shown by the US opioid epidemic; [92]), robust efficacy, and long history of clinical use [93].

The prevalence of 'non-aspirin' NSAID use has been well studied and is dynamic across age, body mass index and geographical ancestry, ranging between ~15-45%, women being the highest users and ibuprofen generally being the most reported [94–96]. Short-term use of NSAIDs is particularly prevalent (~50–80% per year) in athletes and soldiers (individuals that may be at risk for acute and chronic musculoskeletal injuries; [97–99]). Extended periods of NSAID treatment (e.g., more

than 3 times per week for more than 3 months per year) have been reported in 10% of adults in the United States [100], a rate that can be expected to increase with age [101].

NSAIDs act primarily by mediating peripheral pain sensitization driven by inflammatory stimuli, such as acute or sport injuries, (osteo)arthritis etc. and are less effective in treating pain due to nerve damage (neuropathic pain). At the point of inflammatory pain, initiated by nociceptive stimuli, NSAIDs augment the experienced nociceptive excitability (peripheral and central sensitization; [102]). NSAIDs work differently to opioids in that they do not block central pathways of nociception, but inhibit the formation of prostanoids via competitive inhibition of arachidonic acid binding to cyclooxygenase enzyme (COX) isoform active sites [103], which sensitise nociceptive pain. There are two cyclooxygenase isoforms that are the targets of NSAIDs; COX-1 that are expressed in most tissues (including the endothelium, monocytes, gastrointestinal epithelial cells, and platelets) and controls the basal production of prostanoids (**Figure 1**) and COX-2 that are not regularly expressed in most tissues but are upregulated in response to and during the inflammatory process (in tissues such as vascular endothelium, rheumatoid synovial, endothelial cells, monocytes, and macrophages) through the actions of various inflammatory mediators such as bacterial endotoxins, tumour necrosis factor-alpha and interleukins [104]. The increase in COX-2 protein levels are the primary driving force for enhanced production of prostanoids at inflammatory sites [105, 106]. The resulting COX-2 products, particularly prostaglandin (PG) E2, potentiate this response, where PGE2 and prostacyclin (PGI2), produced during local inflammation, augment pain signalling by peripheral and central neurons [15]. PGE2 and PGI2 increase the sensitivity of pain receptors (or nociceptors) in the periphery and enhance the activity of various pain mediators [104, 107]. This mechanism propagates via brain derived PGE2 travelling through the blood–brain barrier, via venules, during systemic inflammation and lessens the inhibition of neurons in the hypothalamus [108]. Drugs that inhibit both COX isoforms with comparable potency (i.e. nonselective NSAIDs such as ibuprofen and ketoprofen) tend to preferentially activate the COX-1 pathway, while drugs with intermediate or selective target COX-2 inhibition (such as nimesulide, meloxicam, diclofenac, celecoxib, rofecoxib, etoricoxib, lumiracoxib etc.) have lesser potential for COX-1 activation [109]. This pathway selectivity is of significant importance as both COX isoform elicit different potentially harmful adverse effects.

In a recent meta-analysis (n = 220,000 patients) of placebo-controlled trials, NSAIDs (coxibs, diclofenac, ibuprofen, and naproxen, predominantly COX-1 inhibiters) significantly increased the risk of upper gastrointestinal complications [eg, ulcer perforations, bleeding, obstructions; 110]. The authors also showed an increased risk of major vascular and coronary events with high doses of coxibs and diclofenac while ibuprofen was associated with an increase in major coronary (but not vascular) events comparable with that of coxibs and oral diclofenac (predominantly COX-2 inhibiters; [110]). These data are corroborated with findings from meta-analysis of observational studies showing low risk of upper gastrointestinal complications (aceclofenac, celecoxib, and ibuprofen predominantly COX-2 inhibiters), intermediate risk (diclofenac, meloxicam, and ketoprofen etc.) and high risk (tenoxicam, naproxen, indomethacin, diflunisal, piroxicam, ketorolac, and azapropazone predominantly COX - inhibiters) depending on the NSAID, likely in a dose dependent fashion [111]. Similarly, total daily oral diclofenac had a linear dose dependent relationship cardiovascular event risk [112]. These dose dependencies are likely a product of the relative effectiveness on either COX-1 or COX-2 inhibition [113–116]. As both (non-inhabited) COX-1 and COX-2 produce cytoprotective prostanoids, inhibition of both COX isozymes (induced by NSAIDs) suppress these

**167**

*Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis*

*1.4.3 Paracetamol (acetaminophen, N-acetyl-p-aminophenol; APAP)*

Seretogentic and Endocannabinoid systems [136].

prostanoids and promotes damage to the gastrointestinal tract and cardiovascular tissues [109, 117]. Based on these and other safety findings, the American Heart Association recommends patients take the lowest effective dose of NSAIDs for the

APAP are likely to be the most commonly used pharmaceutical worldwide [119, 120], are expected to reach a global market value of USD 999.4 million in 2020 [121] and is included in the 21st World Health Organisation Model List of Essential Medicines as updated in March 2017 [122]. However, recently there have been debates from the National Institute for Health and Care Excellence, about the relevance of APAP for some conditions [123]. The efficacy of paracetamol to treat chronic pain has been questioned with systematic reviews showing limited (sometimes null) effects on chronic pain in some conditions [120, 124, 125]. Nonetheless, APAP can be beneficial for acute pain, [126–128], similar to NSAIDs and opioids [129–131]. The precise mechanism of action remains unknown, however this is most likely due to the interwoven interactions that APAP have in multiple pain pathways. Our current knowledge suggests that APAPs are metabolised by the liver into p-aminophenol, then bound with arachidonic acid, primarily in the brain, to form AM404 (N- (4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) through fatty acid amide hydrolase (FAAH) activity [132–134]. Like NSAIDs, APAP are analgesic and antipyretic, however APAP lacks peripheral anti-inflammatory properties, therefore act through the central nervous system and not peripheral tissues [135]. Current evidence suggests that there are four metabolic systems that interact to elicit the analgesic and antipyretic properties of APAP, the Eicosanoid, Opioidergic,

Briefly, like NSIADs, APAP can inhibit central cyclo-oxygenases (COX-1, COX-2) including a proposed third isoform COX-3 [137–142]. Although the results are controversial [143] it is thought that they are involved in prostaglandin (PGs) production thus the analgesic mechanism of action. Furthermore, APAP are more effective in environments with low peroxide tone and low arachidonic acid levels, such as in the central nerves system, mainly through local depletion of glutathione leading to decreased production of PGE2 [139]. Considering the antinociceptive effects of APAP, one of the main brain derived metabolites AM404 (N-arachidonoyl-phenolamine) is decrease in the presence of opioid receptor antagonist. AM404 inhibits the nociceptive activity of particular APAPs in part by modulating many neurotransmitters, including 5-HT, glutamate, and γ-aminobutyric acid [143–145]. Although the precise receptors have not been identified [146–149], serotonin antagonists block the analgesic effect of APAP through mainly indirect non-binding mechanisms [146, 150]. One possible interaction with the serotonergic pathway maybe though altering CNS monoamine neuron types in the brain that contain a major receptor for PGE2 (EP3 receptor [139]). Further to the above, AM404 can inhibit anandamide [151], with stimulation of (canobinoide 1) CB1 receptor activity (without binding) via FAAH [133], suggesting a reliance of APAP antinociceptive activity on interaction with the endocannabinoid system [134, 152]. Interestingly, AM404 is not identifiable in the blood after APAP administration [133] which might explain, to some degree, the absence of peripheral anti-inflammatory action [134]. This could help to explain why APAP may not have significant clinical effect on conditions such as osteoarthritis (further details below; [153, 154]). A recent study confirmed that APAPs act mainly on central analgesic pathways, showing that APAP modifies the activity and connectivity of analgesia via FAAH, activating a signalling cascade involving TRPV1 channels, mGlu5

*DOI: http://dx.doi.org/10.5772/intechopen.95919*

shortest duration of time [118].

#### *Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.95919*

*Pain Management - Practices, Novel Therapies and Bioactives*

isoform elicit different potentially harmful adverse effects.

In a recent meta-analysis (n = 220,000 patients) of placebo-controlled trials, NSAIDs (coxibs, diclofenac, ibuprofen, and naproxen, predominantly COX-1 inhibiters) significantly increased the risk of upper gastrointestinal complications [eg, ulcer perforations, bleeding, obstructions; 110]. The authors also showed an increased risk of major vascular and coronary events with high doses of coxibs and diclofenac while ibuprofen was associated with an increase in major coronary (but not vascular) events comparable with that of coxibs and oral diclofenac (predominantly COX-2 inhibiters; [110]). These data are corroborated with findings from meta-analysis of observational studies showing low risk of upper gastrointestinal complications (aceclofenac, celecoxib, and ibuprofen predominantly COX-2 inhibiters), intermediate risk (diclofenac, meloxicam, and ketoprofen etc.) and high risk (tenoxicam, naproxen, indomethacin, diflunisal, piroxicam, ketorolac, and azapropazone predominantly COX - inhibiters) depending on the NSAID, likely in a dose dependent fashion [111]. Similarly, total daily oral diclofenac had a linear dose dependent relationship cardiovascular event risk [112]. These dose dependencies are likely a product of the relative effectiveness on either COX-1 or COX-2 inhibition [113–116]. As both (non-inhabited) COX-1 and COX-2 produce cytoprotective prostanoids, inhibition of both COX isozymes (induced by NSAIDs) suppress these

age [101].

than 3 times per week for more than 3 months per year) have been reported in 10% of adults in the United States [100], a rate that can be expected to increase with

NSAIDs act primarily by mediating peripheral pain sensitization driven by inflammatory stimuli, such as acute or sport injuries, (osteo)arthritis etc. and are less effective in treating pain due to nerve damage (neuropathic pain). At the point of inflammatory pain, initiated by nociceptive stimuli, NSAIDs augment the experienced nociceptive excitability (peripheral and central sensitization; [102]). NSAIDs work differently to opioids in that they do not block central pathways of nociception, but inhibit the formation of prostanoids via competitive inhibition of arachidonic acid binding to cyclooxygenase enzyme (COX) isoform active sites [103], which sensitise nociceptive pain. There are two cyclooxygenase isoforms that are the targets of NSAIDs; COX-1 that are expressed in most tissues (including the endothelium, monocytes, gastrointestinal epithelial cells, and platelets) and controls the basal production of prostanoids (**Figure 1**) and COX-2 that are not regularly expressed in most tissues but are upregulated in response to and during the inflammatory process (in tissues such as vascular endothelium, rheumatoid synovial, endothelial cells, monocytes, and macrophages) through the actions of various inflammatory mediators such as bacterial endotoxins, tumour necrosis factor-alpha and interleukins [104]. The increase in COX-2 protein levels are the primary driving force for enhanced production of prostanoids at inflammatory sites [105, 106]. The resulting COX-2 products, particularly prostaglandin (PG) E2, potentiate this response, where PGE2 and prostacyclin (PGI2), produced during local inflammation, augment pain signalling by peripheral and central neurons [15]. PGE2 and PGI2 increase the sensitivity of pain receptors (or nociceptors) in the periphery and enhance the activity of various pain mediators [104, 107]. This mechanism propagates via brain derived PGE2 travelling through the blood–brain barrier, via venules, during systemic inflammation and lessens the inhibition of neurons in the hypothalamus [108]. Drugs that inhibit both COX isoforms with comparable potency (i.e. nonselective NSAIDs such as ibuprofen and ketoprofen) tend to preferentially activate the COX-1 pathway, while drugs with intermediate or selective target COX-2 inhibition (such as nimesulide, meloxicam, diclofenac, celecoxib, rofecoxib, etoricoxib, lumiracoxib etc.) have lesser potential for COX-1 activation [109]. This pathway selectivity is of significant importance as both COX

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prostanoids and promotes damage to the gastrointestinal tract and cardiovascular tissues [109, 117]. Based on these and other safety findings, the American Heart Association recommends patients take the lowest effective dose of NSAIDs for the shortest duration of time [118].
