Cannabinoids and Their Effects on Painful Neuropathy

C H A P T E R

94 Cannabinoids and Their Effects on Painful Neuropathy D. Selvarajah*, R. Gandhi**, S. Tesfaye** *Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom **Academic Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom

SUMMARY POINTS • Chronic neuropathic pain is a common and poorly managed condition. • This chapter focuses on the effects of cannabinoids on neuropathic pain. • There is considerable anecdotal and preclinical trial evidence supporting a possible beneficial role for cannabinoids. • However, there have only been a limited range of short-term clinical trials with largely disappointing outcomes. The long term efficacy of cannabinoids have also not been established. • By far the largest numbers of clinical trials conducted to date have examined the use of cannabinoids in central neuropathic pain caused by multiple sclerosis. • There is a restricted role for cannabinoids in certain patient groups with severe painful neuropathy who are inadequately treated on currently available treatments • Further adequately powered clinical trials are required to fully examine the long term safety and efficacy on pain and functional measures of these compounds.

KE Y FA CTS O F PA I NF UL NE URO PATHY • Neuropathic pain is a chronic painful condition that results from damage or dysfunction to the nervous system. • Patients often report a number of typical painful symptoms which includes burning, sharp shooting pain, electric shocks, pins, and needles or tingling. • Chronic neuropathic pain often results in considerable distress and disability leading to significant morbidity and reduction in quality of life. • There is often accompanying mood disorders and sleep disturbance. • Chronic neuropathic pain can be a challenge to manage. Unfortunately, pharmacological therapies are often ineffective and their use is limited by intolerable side effects. • Patients are often managed by a multi-disciplinary team of specialists with a combination of pharmacotherapy, psychological treatment, physiotherapy, and neuromodulation.

LIST OF ABBREVIATIONS 2-AG 2-Arachidonoylglycerol CBME Cannabis based medicinal extract CNS Central nervous system

Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00109-5 Copyright © 2017 Elsevier Inc. All rights reserved.

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DN Diabetic neuropathy EMEA European Medicines Agency FDA Federal Drug Administration HIV Human immunodeficiency virus HIV-PN Human immunodeficiency virus painful neuropathy MS Multiple sclerosis THC Tetrahydrocannabinol

INTRODUCTION Neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system” (Treede et al., 2008), and is estimated to affect up to 7–8% of the general population in Europe (Torrance, Smith, Bennett, & Lee, 2006). A number of different pathological processes that cause neuronal dysfunction can lead to neuropathic pain (Table 94.1). Common examples include diabetic polyneuropathies, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and postsurgical/traumatic neuropathies. Regardless of etiology, chronic neuropathic pain often results in considerable distress and disability leading to significant comorbidity and an overall reduction in an individual’s quality of life (Meyer-Rosberg et al., 2001). This leads to mood disorders, pathological sleep states (Gore et al., 2005), and social isolation (McCarberg & Billington, 2006). The management of patients with neuropathic pain is challenging, as current pharmacological treatments are often ineffective and use limited by intolerable side effects (Finnerup, Sindrup, & Jensen, 2010; Attal et al., 2010; Dworkin et al., 2007).

TABLE 94.1 Common Causes of Neuropathic Pain Metabolic/ nutritional

Diabetes mellitus, uremia, vitamin B12 and folate deficiencies, paraneoplastic, hypothyroidism

Toxic/drug related

Alcohol, antiretroviral drugs, antituberculosis drugs, chemotherapy (vincristine, cisplatinum, paclitaxel), fluoroquinolones

Viral

Human immunodeficiency virus, herpes zoster, and postherpetic neuralgia

Structural/ pressure/ trauma

Postsurgical/traumatic neuropathies, entrapment syndromes, neuropathic lower back pain, phantom limb pain, nerve root syndromes/ radiculopathies, radiotherapy

Inflammatory Vasculitis, Sjogren’s syndrome, systemic lupus erythematosus Others

Complex regional pain syndrome, ischemic neuropathies, neuromas, multiple-sclerosis vascular brain/spinal cord lesions (brainstem/ thalamic)

The discovery of cannabinoid receptors and their endogenous ligands has resulted in a number of clinical trials involving cannabinoids in neuropathic pain. Presently, in the United Kingdom, the only approved indication for cannabinoids is for neuropathic pain and muscle spasticity in multiple sclerosis (MS) (Guindon & Hohmann, 2008). Uncertainties remain for its use in other neuropathic pain conditions. This chapter will examine the pathophysiology and mechanisms of neuropathic pain and review the existing literature on cannabinoid use in painful neuropathy.

NEUROPATHIC PAIN MECHANISMS Despite the broad spectrum of etiologies, the clinical manifestations of neuropathic pain are similar across the different syndromes. This is because the symptoms and signs of neuropathic pain are caused by a combination of abnormal nerve activity (ectopic activity and central sensitization) and lesion-induced reduced sensations (Table 94.2) (Baron, Binder, & Wasner, 2010). Detailed history and clinical examination aimed at identifying these characteristic symptoms and sensory abnormalities are important for the accurate diagnosis of neuropathic pain and to distinguish this from other pain types.

PATHOPHYSIOLOGY OF NEUROPATHIC PAIN Over the past decade, pain research has made considerable progress to uncover the pathophysiology of neuropathic pain (Fig. 94.1) (Baron et al., 2010). Although this has led to a better mechanistic understanding into human pain pathology, there is still a lack of effective mechanism-based treatment approaches and more efficient analgesia. According to data from basic research and human pain experiments a lesion to the afferent pathway is necessary for the development of neuropathic pain (Baron, 2006). This triggers a cascade of several different mechanisms leading to neuropathic pain. Different mechanisms can be involved in the same disease or in the same individual which could in turn lead to the same symptom (Baron et al., 2010). For example, on-going spontaneous pain and paroxysmal TABLE 94.2 Symptoms and Signs of Neuropathic Pain Positive symptoms and signs: • Spontaneous: burning pain, paresthesia, sharp shooting pain, electric shocks • Evoked pain: allodynia, hyperalgesia Negative symptoms and signs: • Hypoalgesia and hypoesthesia

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FIGURE 94.1  Pathophysiological mechanisms of neuropathic pain. (A) Primary afferent pathways and their connections in the spinal cord dorsal horn. Nociceptive C-fibers (red) terminate at spinothalamic projection neurons in the upper laminae (yellow neuron). Nonnociceptive myelinated A-fibers project to deeper laminae. The second-order projection neuron receives direct synaptic input from nociceptive terminals and also multisynaptic input from myelinated A-fibers (nonnoxious information, blue neuron system). Interaction with microglial (gray cell) facilitates synaptic transmission. GABAergic interneurons (green neuron) normally exert inhibitory synaptic input on second order neuronal projections. (B) Peripheral changes at primary afferent neurons after a partial nerve lesion, leading to peripheral sensitization. Note that some axons are damaged and degenerate (axons 1 and 3) and some are still intact and connect to the peripheral end organ (skin; axons 2 and 4). Expression of sodium channels is increased on damaged neurons (axon 3), triggered has a consequence of the lesion. Furthermore, products such as nerve growth factor, associated with Wallerian degeneration and release in the vicinity of spared fibers (arrow), trigger expression of channels and receptors (eg, sodium channels, TRPV1 receptors, adrenoreceptors) on uninjured fibers. (C) Spontaneous activity in C-nociceptors induces secondary changes in central sensory processing, leading to spinal cord hyperexcitability (central sensitization of second-order nociceptive neurons, star in yellow neuron) that causes input from mechanoreceptors A-fibers (blue neuron system, light touching and punctuate stimuli) to be perceived as pain (dynamic and punctate mechanical allodynia, + indicates gating at synapse). Several presynaptic (opioid receptors, calcium channels) and postsynaptic molecular structures (glutamate receptors, AMPA/kainite receptors, sodium/5HT receptors, GABA receptors, sodium channels) are involved in central sensitization. Inhibitory interneurons and descending modulatory control systems (green neurons) are dysfunctional after nerve lesions, leading to disinhibition or facilitation of spinal cord dorsal horn neurons and to further central sensitization. (D) Peripheral nerve injury activates spinal cord glial cells (gray cell) via chemokines, such as CCL2 acting on chemokine receptors. Activated microglia further enhance excitability in second order neuronal projections by releasing chemokines and growth factors (eg, tumor necrosis factor, bone-derived nerve factor) and increasing glutamate concentrations. Source: Adapted from Baron et al. (2010).

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shooting pain is the result of abnormal ectopic nociceptive nerve activity. Under normal physiologic conditions these unmyelinated c-fiber and thinly myelinated Aδ afferent nociceptive fibers usually have a high threshold for activation to indicate potential tissue damage. In neuropathic pain states, this threshold is lowered and results in spontaneous activity (Ørstavik et al., 2006; Ørstavik & Jørum, 2010; Nyström & Hagbarth, 1981). Changes in the voltage gated sodium channels, potassium channels, and upregulation of receptor proteins (eg, TRPV1) have all been shown to correlate with increased spontaneous nerve activity (Caterina & Julius, 2001; Fischer & Reeh, 2007; Ma, Zhang, Bantel, & Eisenach, 2005). Secondary allodynia and hyperalgesia on the other hand occurs as a result of involvement of the central nervous system (CNS) (Baron et al., 2010). In a process called central sensitization, lesions within first order afferent neurons induce postsynaptic changes within second-order nociceptive neurons that lowers the mechanosensitivity threshold of Aβ and Aδ afferent fibers (Hains, Saab, Klein, Craner, & Waxman, 2004; Ultenius, Linderoth, Meyerson, & Wallin, 2006). As a result, nonpainful tactile stimulation (light brushing) becomes painful. These mechanisms are thought to occur at both spinal and supraspinal levels of the CNS. These processes highlight clearly the complexity of neuropathic pain and the challenges posed to develop therapeutic regimens that are effective at treating and preventing this condition. Further research is needed to identify the mechanisms involved for an individual patient as this could lead to targeted treatment regimens for the different pain mechanisms. One of the earliest documented uses of cannabis was in pain management. It was used for surgical anesthesia in ancient China and for pain relief in early Egyptian, Roman, and Indian civilizations (Peters & Nahas, 1999). More recent experimental studies in animal models of pain have demonstrated beneficial antinociceptive effects and provide substantial preclinical evidence (Guindon & Hohmann, 2009; Hohmann & Suplita, 2006). In a wide range of animal models of neuropathic pain, various studies have demonstrated that cannabinoid agonists reverse the common symptoms of neuropathic pain, including allodynia and hyperalgesia. In these studies, the analgesic properties of cannabinoids depend on a number of factors including administration route, assay conditions and the preparation of the drug (Harris, 1971). Of these factors, route of administration plays a critical role; when given intravenously, THS exhibits high degree of potency and efficacy comparable to morphine. In contract the efficacy of THC is considerably reduced when administered subcutaneously or intraperitoneally. Administration of cannabinoids to animals also elicits a number of significant adverse effects including sedation, motor, and cognitive impairments (Little,

Compton, Johnson, Melvin, & Martin, 1988). Such side effects could potentially confound the interpretation of antinociceptive measurements in animal studies which generally rely on paw/tail withdrawal from a noxious stimulus. Thus, it remains to be determined if cannabinoids can produce pain relief at doses below the side effect threshold. The analgesic properties of cannabinoids occur through a complex range of mechanisms at different levels of the nervous system. This is consistent with the presence of CB1 and CB2 receptors in three key areas involved in pain control (peripheral, spinal, and brain) (Agarwal et al., 2007; Herkenham, 1995; Van Sickle et al., 2005; Jhaveri, Sagar, Elmes, Kendall, & Chapman, 2007). These include the periaqueductal gray, spinal dorsal horn and dorsal root ganglion and are target sites of major ­endocannabinoids, such as Narachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG). They may also modulate analgesic responses via noncannabinoid receptor targets (eg, anandamide is also a ligand for the TRPV-1 receptor) (Cristino et al., 2006; Ahluwalia, Urban, Capogna, Bevan, & Nagy, 2000) and by working synergistically with the endogenous opioid system (Pertwee, 2001). Both endogenous cannabinoid and opioid systems display similarities in receptor structure and signal transduction (Fig. 94.2). Stimulation of these receptors blocks the conversion of noxious stimuli into electrochemical signals by inhibiting voltage-gated Ca2+ channels, stimulating K+ inward channels, and subsequently inhibiting the Ca2+ dependent release of pronociceptive effectors such as substance P, calcitonin gene-related peptide, and bradykinin (Roques, Fournié-Zaluski, & Wurm, 2012).

PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN Treatment of chronic neuropathic pain can be one of the most challenging areas of modern medical practice. In addition to suffering longstanding disabling pain, patients often have complex biological, psychological, and social problems. Their pain has often been diagnosed incorrectly and managed poorly. Pharmocotherapy remains the main pillar of pain management and can be divided into two broad classes, membrane stabilizing agents (antiepileptic drugs and anesthetics) and medications that enhance dorsal horn inhibitory mechanisms (Table 94.3) (Attal et al., 2010). Most agents, however, have multiple mechanisms of action and their effects often may overlap. Despite being the mainstay in the management of neuropathic pain, there are significant limitations to currently available pharmacological treatments. Lack of perceived efficacy,

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Multiple sclerosis central painful neuropathy

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FIGURE 94.2  Endogenous cannabinoids and opioids are present at all three levels of pain control. Endogenous opioids and endogenous cannabinoids are distributed widely in the CNS, spinal cord, and peripheral organs. At the periphery, endogenous opioids, and endogenous cannabinoids are present in epithelial cells of the intestine and kidney, in the joints, lung, testis, and skin, as well as on various types of immune cells, including oligodendrocytes and Schwann cells surrounding nerve fibers. Cannabinoid receptors are found at the nociceptor level, and in immune cells, where inhibitors can block the noxious inputs. Noxiously stimulated cutaneous fibers converge to the dorsal horn, sometimes along with nonstimulated fibers from distant cutaneous, muscular or visceral areas. µ-opioid receptors (MORs) and δ-opioid receptors (DORs) are mainly located at the presynaptic end of afferent fibers in the spinal dorsal horn. The brain distribution of MORs and DORs are in structures involved in the control of pain and emotions, such as the periaqueductal gray, thalamus, cortex, and limbic system. Brain neurons enriched in cannabinoid receptor 1 (CB1R), includes structures involved in fear and emotions. Source: Adapted from Roques et al. (2012).

TABLE 94.3 Pharmacological Treatments for Neuropathic Pain Anticonvulsants

Gabapentin, pregabalin, carbamazepine, oxcarbazepine, topiramate, lamotrigine

Antidepressants • Selective serotonin and noradrenaline reuptake inhibitor • Tricyclic antidepressants

Duloxetine, venlafaxine Amitriptyline, imipramine, nortriptyline

Opioids

Tramadol, morphine, oxycodone

unpleasant side effect profiles, drug interactions, and costs are some of the factors that limit the use of these agents. As a result patients with intractable neuropathic pain are often managed in a patient focused multidisciplinary approach which include attempts to treat the underlying disease (eg, diabetes), a rational titrated approach to medications, neuromodulation (eg, ablation therapy, or spinal cord stimulation), psychological, and physical therapies (Fig. 94.3) (Turk & Melzack, 2011).

CANNABINOIDS AND NEUROPATHIC PAIN Cannabinoids have been evaluated in a number of different clinical pain studies for their effectiveness on acute postoperative and chronic neuropathic pain. These studies indicate that cannabinoids exhibit their greatest efficacy when employed in the management of neuropathic pain (Dyer, 2013). A number of different preparations and delivery methods (oral-mucosal spray and rectal suppositories—benefit of rapid action) have been examined in these clinical trials. This makes any direct comparisons difficult. For example, there are 460 known chemical constituents in cannabis and as a result the pharmacological properties of smoking cannabis are different from oral preparations of ∆9-THC or different combinations of ∆9-THC and cannabidiol (Huesis, 1999).

MULTIPLE SCLEROSIS CENTRAL PAINFUL NEUROPATHY By far, the largest numbers of disease-related clinical studies conducted to date assessing the effects of cannabinoids have been in central neuropathic pain caused

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FIGURE 94.3  Approach to the management of neuropathic pain. The management of neuropathic pain should follow a two-pronged approach. Following diagnosis of chronic neuropathic pain, efforts should focus on treating (if possible) the underlying condition to prevent further progression of disease. At the same time, appropriate symptomatic treatment should be offered to reduce pain. The aim of symptomatic treatment should not only focus on pain relief but also improve an individual’s physical functioning, reduce any emotional distress, and improve sleep duration and quality. This will ultimately result in an overall improvement in an individual’s quality of life. Source: Adapted from Turk and Melzack (2011).

by multiple sclerosis. Most of these studies, however, focused on the treatment of spasticity. Altogether, there are three Class I, two Class II and four Class III studies of cannabinoids which also included treating central neuropathic pain (either as a secondary end-point or incorporated as part of a composite score) between 1970 and Sep. 2013 (Yadav et al., 2014). These studies were included in a systematic review by the Guideline Development Subcommittee of the American Academy of Neurology which concluded that for patients with MS with central neuropathic pain or painful spasms, oral cannabinoid extract is effective for reducing central pain. Tetrahydrocannabinol and nabiximols were probably effective in treating MS-related pain or painful spasms. Standard medical therapy was continued in these studies, so no comment was made as to comparative effectiveness. This restricts the use of cannabinoids in multiple sclerosis (Level A) only if other treatments fail. It is difficult to tease out the clinical effectiveness of cannabinoids on the neuropathic pain components in many of these trials in the presence of both painful spasticity and dysesthesia. Some authors view spasm-related pain in multiple sclerosis as being neuropathic whereas others do not. Post-hoc attempts to examine the efficacy of cannabinoids on the different pain manifestation in multiple sclerosis have suggested that both components respond similarly to treatment (Rog, Nurmikko, Friede, & Young, 2005). Hence, from a patients’ perspective such comparisons may be unnecessary. Two notable Class 1 studies have evaluated the efficacy of cannabinoids on central neuropathic pain in multiple sclerosis. Rog et al. (2005) reported a single-center 4-week treatment randomized, double-blind, placebo-controlled trial in 66 patients with MS and central pain

states (based on pain description and clinical examination, painless spasms excluded) of nabiximols (2.7 mg THC: 2.5 mg CBD, cannabis based medicinal extract, CBME) oromucosal spray as adjunctive analgesia. They demonstrated that treatment with nabiximols resulted in significant reduction in mean pain intensity [11-point numeric rating scale (NRS-11); nabiximols mean change –2.7, 95% CI: –3.4 to –2.0 vs placebo –1.4 (–2.0:–0.8); p = 0.005] and sleep disturbance [–2.5 (–3.4:– 1.7) vs –0.8 (–1.5:–0.1); p = 0.003], when compared to placebo. Overall, nabiximol treatment was generally well tolerated, although more patients on active treatment reported dizziness, dry mouth, and somnolence compared with placebo. Patients in this study were taking on average, two other medications, with limited efficacy given baseline NRS-11 pain scores of 6.5. This would suggest as adjunctive treatment nabiximol treatment resulted in a significant treatment effect of –1.3 in the NRS-11 pain scores. Svendsen, Jensen, and Bach (2004) reported a randomized, placebo-controlled crossover study to evaluate the effect of oral synthetic ∆9-THC dronabinol on central neuropathic pain. In total, 24 patients with MS and central pain (based on clinical examination or quantitative sensory testing) received dronabinol (10 mg OD max) or placebo for 3-weeks separated by a 3-week wash-out period. Dronabinol treatment resulted in significantly lower spontaneous pain intensity compared to placebo treatment [4.0 (25th–75th CI: 2.3–6.0) vs 5.0 (4.0:6.4); p = 0.02]. The estimated difference between dronabinol and placebo treatments was –0.6 (95% CI: –1.9 to 0). Lower median radiating pain intensity and higher pain relief score was obtained during the last week of dronabinol treatment compared to placebo. Interestingly, there was a significantly higher pressure

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HIV painful neuropathy

pain threshold during dronabinol treatment (secondary outcome which was not subjected to correction for multiple comparisons) but no differences between treatments in cold sensibility, warm sensibility, tactile detection, tactile pain detection, vibration sense, temporal summation, or mechanical and cold allodynia. Adverse events were more common in the dronabinol treatment (96%) than during placebo treatment (46%). The most common adverse events during active treatment were dizziness, headaches, tiredness, myalgia, and muscle weakness. Overall, dronabinol has a modest analgesic effect on central pain in multiple sclerosis patients. Although the effect size is less than the nabiximol used by Rog et al. (2005) this should be interpreted with caution given the different study designs. Both treatments result in modest improvements in pain which arguably are a clinical relevant analgesic effect in MS patients with central pain. Although, it is suggested that a 30% or 2-point NRC score reduction in pain as being clinically significant, both studies included patients whose pain was controlled poorly on existing medications and even a relatively small reduction in pain intensity are often very appreciated by the patients. Both effect sizes are comparable to other treatment options available with numbers needed to treat to obtain one patient with more than 50% pain relief of 3.45 and 3.7 for dronabinol and CBME respectively (Sindrup & Jensen, 1999). Systematic reviews of trials of cannabinoids in participants with other types of neuropathic pain have reported mixed results.

HIV PAINFUL NEUROPATHY Distal symmetrical painful peripheral neuropathy is a frequent complication of HIV infection. Its prevalence is increasing despite (or because of) the introduction of otherwise successful antiretroviral therapy (Evans et al., 2011). The accompanying pain has a major impact on quality of life in otherwise largely healthy individuals. There are at least two etiologies that often coexist and are clinically indistinguishable (Pardo, McArthur, & Griffin, 2001). One associated with HIV disease itself and the other which complicates antiretroviral treatments. Both etiologies cause a distal symmetrical axonal sensory polyneuropathy that affects the feet and less frequently the hands. Often only a temporal association between the onset of symptoms and the starting of a particular antiretroviral agent will provide clues to the possible etiology. A recent systematic review and metaanalysis of randomized control trials was performed to evaluate the clinical effectiveness of analgesics for the treatment of painful HIV painful neuropathy (HIV-PN) (Phillips, Cherry, Cox, Marshall, & Rice, 2010). Of 44 studies identified only 14 met the inclusion criteria for metaanalysis.

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Authors reported evidence of efficacy only exists for smoked cannabis, capsaicin 8% topical cream, and recombinant human growth factor (clinically unavailable). The evidence for effectiveness of cannabis was based on two randomized clinical trials: Ellis et al. (2008) reported on the double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis on neuropathic pain in HIV infection. Patients (n = 34) had intractable painful neuropathic symptoms refractory to at least two previous analgesic classes and consumed between 1% and 8% ∆9-THC, 4 times daily for 5 consecutive days during a 2-week treatment phase. Active and placebo treatment was separated by a 2-week washout. Pain relief as assessed by the descriptor differential scale was greater in with cannabis than placebo (median difference DDS pain score change, 3.3 points, p = 0.02) among the completers [28 out of 34 subjects randomized (21.4% dropout)]. Proportion of subjects achieving at least 30% reduction in pain intensity with cannabis versus placebo were 0.46 (95% CI: 0.28–0.65) and 0.18 (0.03:0.32) respectively. Sensitivity analysis was performed to examine if blinding was preserved over the course of the study. When subjects were on placebo, accuracy of treatment guesses was no different from random guessing (50%), however, the majority of subjects (93%) were able to guess correctly during the cannabis treatment period. Hence, there was a high risk of performance and detection bias. Abrams et al. (2007) compared smoked cannabis (3.56% ∆9-THC tds) to placebo cigarettes in a parallel group RCT design. Only subjects with previous exposure to cannabis were included in this study (n = 27). Those who were current users were asked to discontinue prior to study. Again there was a significant reduction in overall pain intensity from baseline in the cannabis treated group at the end of Day 5 of treatment. A greater proportion of subjects in the cannabis treated group (13/27) reported at least a 30% reduction in VAS pain intensity compared to placebo (6/27). Sensitivity analysis was not performed to assess the robustness of placebo control. It is possible given subjects had a history of previous exposure to cannabis that unintentional unblinding may have occurred during the course of the study. Based on these two studies, the NNT for smoked cannabis was calculated as 3.38 (95% CI: 2.19–7.5). Smoking cannabis should not be clinically advocated. Further well designed clinical trials using alternative routes of administration should be assessed. Both these studies are also limited by small sample sizes, short duration, and restricted subject selection which limits the generalizability of reported findings. They do, however, suggest a “proof of concept” that cannabinoid therapy may be an effective option for pain relief in HIV-PN patients, which needs further investigation.

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DIABETIC DISTAL SYMMETRICAL SENSORIMOTOR POLYNEUROPATHY Diabetes affects approximately 415 million people worldwide (http://www.idf.org/worlddiabetesday/ toolkit/gp/facts-figures). This is expected to rise considerably within the next 10 years. Complications of diabetes cause great distress, premature death, and disability to subjects, and is a major burden on national health services. Diabetic neuropathy is one of the commonest long-term complications of diabetes with a prevalence rate of up to 50% after 15–20 years of the disease (Dyck et al., 1993). Painful neuropathy (painful DN) will affect 10% of all subjects with diabetes and causes great distress and disability to sufferers and affects quality of life immensely (Galer, Gianas, & Jensen, 2000). Usually, if the pain persists for longer than 12 months it does not resolve and may thus last for many years. Apart from strict glycemic control there are no pharmacological therapies that have been proven to halt or reverse the neuropathic process. Unfortunately, additional drug treatments used to alleviate painful symptoms are often ineffective and complicated by side effects. A recent metaanalysis of randomized controlled trials for the treatment of painful DN has reported that at best less than a third of patients achieve at least a 30% reduction in pain intensity (Snedecor et al., 2014). Occasionally, in subjects who do not respond to drug treatment electrical spinal cord stimulation has been used. Two small studies have examined the use of cannabinoids in painful DN. Selvarajah, Gandhi, Emery, and Tesfaye (2010) conducted a randomized, placebo-controlled, double-blind, controlled trial to assess the efficacy of Sativex, a cannabis based medicinal extract, as adjunctive treatment in painful DN. In this small study, 30 subjects were randomized to receive daily sativex or placebo. There was significant improvement in pain scores in both groups, but mean change between groups was not significant. In addition to a large placebo response, post-hoc analysis revealed that subjects with greater depressive symptoms reported higher pain scores at baseline and they improved regardless of intervention. In this first-ever trial assessing the efficacy of cannabis in painful DN showed it to be no more efficacious than placebo. The main limitations of this study were the small sample size and the use of concomitant medications which may have attenuated the analgesic response to sativex. In a subsequent study adopting a different trial design, Toth et al. (2012) reported evaluated add-on treatment of oral cannabinoid, nabilone, for refractory painful DN. They conducted a single center, enriched enrolment, placebo controlled, randomized withdrawal study. 37 subjects with pain scores greater than 4 (0–10 scale) received, single blinded adjuvant nabilone for 4 weeks. Subjects achieving greater than 30% pain relief (responders) were

then randomized to either continue on going nabilone treatment or switch to placebo. Although, the study failed to randomize the number of subjects estimated by initial sample size calculation, it reported significant reduction in pain intensity with nabilone treatment compared to placebo in “responders.” The number of subjects with more than 30% reduction in pain from baseline to endpoint was 11/13 (85%) in the nabilone group compared to 5/13 (38%) in the placebo group (p < 0.05). There were also improvements in anxiety scores, well-being, and sleep disturbance with nabilone treatment. Demonstration of improvement in these multiple measures adds veracity to study findings. However, the overall effect size was small (0.67) for nabilone compared to placebo despite the enriched study design, which also limits the generalizability of study findings. Both studies are limited by the relatively small sample sizes, short duration of follow-up, and risk of inadvertent unmasking with the enriched trial design. Once again, larger, well designed, adequately powered studies are required to truly examine the analgesic effects of cannabinoids in painful DN.

SPINAL CORD INJURY A systematic review and metaanalysis of drugs for neuropathic pain associated with spinal cord injury examined nine placebo control trials which included one small crossover trial which evaluated dronabinol (n = 7) (Snedecor et al., 2013; Rintala, Fiess, Tan, Holmes, & Bruel, 2010). In this pilot study, the effects of dronabinol were comparable to an active placebo diphenhydramine (an antihistamine which does not possess analgesic properties but mimics some of the possible side effects of cannabinoids). On average, dronabinol was no more effective than diphenhydramine for relieving chronic neuropathic pain below the level of injury. There have been very few head-to-head studies of cannabinoids with other analgesic treatments in neuropathic pain. One notable study compared dihydrocodeine and nabilone in a randomized, double blind, crossover trial of 14 weeks duration (Frank, Serpell, Hughes, Matthews, & Kapur, 2008). Ninety six subjects with neuropathic pain (confirmed on clinical examination) of mixed etiologies (majority 42/96 were nerve injury postsurgery) were randomized. There was a high drop-out rate which can be explained partially by the crossover design. The weak opioid dihydrocodeine was found to provide better pain relief than the cannabinoid in the treatment of chronic neuropathic pain [mean difference in 10.0 cm VAS between nabilone and dihydrocodeine was in favor of the latter: 0.6 cm (95% CI: 1.4–10.5), p = 0.01]. Dihydrocodeine use was also accompanied by fewer side effects, although no major adverse events occurred for either drug. Overall, there is a lack of clinical studies as well as a dearth

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Conclusions

of comparative data with different pharmacologic therapies. As such, the effectiveness of cannabinoids in the treatment of other neuropathic pain remains unproven.

SIDE EFFECTS Side effects were reported in all studies in a proportion of patients receiving cannabinoids. In the recent systematic review of cannabinoids in chronic noncancer pain, of the 18 trials examined there were no serious adverse events (Lynch & Campbell, 2011). Drug-related adverse events were generally described as well tolerated, transient or mild to moderate. Most frequently reported side effects were dizziness, loss of balance, feelings of intoxication, dry mouth, gastrointestinal effects, sedation, and hunger. In the longest extension study (up to three years) to date these side effects were reported by 90% of patients and no tolerance was observed (Wade, Makela, House, Bateman, & Robson, 2006). Most clinical studies however treated patients for less than 6 months and report a greater proportion of patients discontinuing medications because of adverse events in the active treatment group compared to placebo. Data on the symptoms that cause withdrawal of medications are often incomplete. Among patients treated with cannabinoids, this could either be a direct result of adverse events related to the drug or an indirect effect caused by interactions with other medications being taken, especially opiates for pain or a combination of both (Sutin & Nahas, 1999). Hence, adverse events are a significant concern with cannabinoid use especially in high risk populations with multiple medical comorbidities and polypharmacy. Hence, individual circumstances (medical and social) should be carefully considered when selecting potential patients for treatment. If medical use is likely to be long-term, patients should be warned that the adverse effects of long-term use are unclear, including the risk of dependence and cognitive impairment. It may be sensible to refer patients to specialist management of the condition, where trial of cannabinoids might be undertaken (Farrell, Buchbinder, & Hall, 2014).

FUTURE CLINICAL STUDIES As highlighted earlier, there is a need for more robust, well-powered, randomized controlled clinical trials of cannabinoids (either vs placebo or head-to-head studies against established neuropathic pain treatments) in different models of neuropathic pain. Based on the currently available published literature, cannabinoids have at best only a modest effect on neuropathic pain, comparable to other established pharmacological therapies. One possible reason for this may be related to the fact that in most studies a summative pain score is used as the

primary outcome. This does not sufficiently consider the heterogeneity of neuropathic pain syndromes. Hence, a comprehensive assessment of symptoms and signs of pain could be a more sensitive way than an overall assessment of pain in demonstrating and characterizing the effects of a given pharmacological treatment (Attal et al., 2011; Baron, Förster, & Binder, 2012). For example, studies have demonstrated that morphine and lidocaine act differently on different neuropathic pain symptoms and signs as captured using quantitative sensory testing and/or neuropathic pain questionnaires that better quantify the heterogeneity of neuropathic pain syndromes (Attal et al., 2002, 2000). A post-hoc analysis performed in the Combination versus monotherapy of pregabalin and duloxetine in diabetic neuropathy study (COMBO-DN) showed that adding pregabalin to existing duloxetine treatment seemed to have benefited those with pressing pain and evoked pain; whereas increasing the dose of duloxetine appeared more beneficial for parethesic/ dysesthesic symptoms (Bouhassira et al., 2014). In the context of cannabinoids, this hypothesis is best supported by the recent demonstration that these agents show greater reduction in mechanical/thermal hyperalgesia and tactile allodynia than placebo. Future studies should explore these hypotheses as this might lead to more stratified treatment and potentially to personalized pain therapy where cannabinoids are most effective. Finally, most studies in neuropathic pain conducted to date have assessed the efficacy of cannabinoids over a relatively short duration. The key question, therefore, is the long-term safety and efficacy of these agents. Large scale, long-term observational outcome studies or record linkage studies based on the use of cannabinoids for medically approved indications such as multiple sclerosis may quantify the risks and benefits of long term use (Farrell et al., 2014). In a recent opinion piece, Farrell et al. (2014) searched key clinical trials registers including US ClinicalTrials.gov, EU Clinical Trials Registry, and Australian and New Zealand Clinical trials Register and found 10 prospective studies of cannabinoids but was unable to identify key studies that would provide important information on the long-term safety and efficacy of these agents in the near future.

CONCLUSIONS Chronic neuropathic pain is a common and poorly managed condition. Currently available treatments are often ineffective with side effect profiles that limit their use. This leads to significant morbidity and poor quality of life. In this context, patients with chronic neuropathic pain require access to better therapeutic care and additional treatment options. Although there is considerable anecdotal and preclinical trial evidence supporting

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an antinociceptive role for cannabinoids, outcomes in the limited range of clinical trials that have been performed thus far have been largely disappointing. Most clinical studies have focused on narrow clinical indications with modest effect sizes not dissimilar to many of the currently used neuropathic pain treatments. As a result, the use of cannabinoids is restricted to specialist use for only a limited range of conditions. Adequately powered, placebo-controlled or head-to-head, multicenter, clinical studies in neuropathy pain models according to predetermined FDA/EMEA guidelines are required in order to fully examine the safety and efficacy on pain and functional measures of these compounds.

MINI-DICTIONARY Adverse events  These are predetermined recorded events that occur to subjects during participation in a clinical trial. Example of such events include hospital admission, injury or harm and death. Allodynia  This is a description of a type of painful symptom that can accompany nerve damage. It occurs when pain is evoked during nonpainful stimulus (eg, soft touch). Electrical spinal cord stimulation  This is a treatment of very severe neuropathic pain in the lower limbs. Low voltage current is delivered by electrodes are placed near the spinal cord. The duration and intensity of the current can be controlled using a portable, remote-control, radio-receiver unit. Hyperalgesia  This is a description of a type of painful symptom that can accompany nerve damage. It occurs when a normally painful stimulus (pressure pain) is report as very painful. Myalgia Symptom of muscle aches and pains. Neuromodulation  Nonpharmacological treatment of neuropathic pain which can include nerve ablation or electrical spinal cord stimulation. Neuropathic pain  Chronic pain that results from nerve damage. This results in a particular description of either spontaneous or evoked painful symptoms, such as, burning, sharp shooting, or deep aching pain. Paresthesia  This is a description of a type of painful symptom that can accompany nerve damage. It is a description of symptoms of pins and needles or tingling. Postherpetic neuralgia  Nerve damage that follow herpes viral infection. Post-hoc analysis Secondary or follow-up analysis performed on clinical trial data. This type of analysis of often not planned at the start of the study but informed by its outcome. Randomized controlled trials  These are clinical trials which are often conducted to investigate the effectiveness of a drug. Subjects are randomized to two (sometimes more) treatment arms to compare the effects of the drug under investigation against either placebo or current treatment. Trigeminal neuralgia  Neuropathic pain/symptoms that occurs as a result of damage to the trigeminal nerve.

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