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Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain

Practice Points

Anoop Kuttikat†1 & Nicholas Shenker1,2 „„ Chronic musculoskeletal pain, defined as pain lasting beyond the usual healing time of 6 weeks to

3 months, is maladaptive. „„ Chronic musculoskeletal disorders have a significant socioeconomic impact and account for

approximately 20% of UK incapacity benefits. „„ Central and peripheral sensitization manifest as pain hypersensitivity and are key mechanisms for the

development of pathological pain. „„ Drugs that modulate central pain processing such as tricyclic antidepressants, serotonin–norepinephrine

reuptake inhibitors, pregabalin and tramadol are useful in treating chronic musculoskeletal pain. „„ Pharmacological agents work best within a holistic approach incorporating self-efficacy

strategies and rehabilitation.


Chronic musculoskeletal pain, defined as pain lasting beyond the usual healing time of 6 weeks to 3 months, is a very common condition. It adversely affects the quality of life of patients and has a significant economic impact on our society. There is an ever increasing understanding of the pathophysiology of chronic pain. This has resulted in the effective use of various medications aimed at modulating both central and peripheral sensitizations. There are also new agents being developed based on fundamental research. The pharmacological agents used in the modulation of central nociception in chronic musculoskeletal pain are reviewed in this article. Pain is the main symptom of most musculo­ skeletal conditions. The musculoskeletal system has abundant specialized receptors called nocicep­ tors that respond to noxious stimuli. They have evolved to protect and prevent any significant tis­ sue damage. This role is clearly illustrated in the rare cases of individuals who cannot feel pain. They sustain serious injuries and in some cases early death [1] .

Chronic musculoskeletal pain is maladaptive and is defined as pain that lasts beyond the healing time, usually 30% reduc­ tion in pain was five [33] . This indicates that drugs targeting central sensitization are efficacious in


Pain Manage. (2011) 1(6)

this patient population. Duloxetine 60 mg daily is approved for fibromyalgia by the US FDA (CEBM level of evidence: Ia). Pregabalin, the first drug to be approved by the FDA for fibromyalgia acts by binding to the a2-d subunit of voltage-gated calcium channel in CNS tissues. The recommended starting dose of pregab­ alin for fibromyalgia is 150 mg/day, which may be titrated up to a maximum of 450 mg/day. Crofford et al. have demonstrated the safety and efficacy of pregabalin in a randomized double blind placebo controlled study for patients with fibromyalgia. The NNT to produce a 50% reduction in pain was six [34](CEBM level of evidence: Ib). Recent studies also suggest that gabapentin, a compound structurally related to pregaba­ lin, is also effective in fibromyalgia. The NNT with gabapentin was five to produce a 30% pain reduction [35] . Dizziness, somnolence and weight gain were the most frequently reported dose related adverse effects with both pregabalin and gabapentin (CEBM level of evidence: Ib). Sodium oxybate is the sodium salt of g-hydroxy­ butyrate which has been found to be effective in treatment of fibromyalgia. The NNT was 4.3 to produce a 30% pain reduction. However due to safety concerns, an advisory FDA committee did not approve its use in fibromyalgia [36] . Conclusion & future perspective In summary, chronic musculoskeletal pain is a common problem causing significant disability to the individuals with huge socioeconomic con­ sequences. There are many treatment options with good evidence for efficacy. There are also new agents arriving and being developed based on the fundamental research advances, which are discussed in the following paragraphs. Management of chronic pain associated with inflammatory conditions should primarily be to control the inflammation. In addition, TNF‑a, IL-1 and IL-6 blockers may all have a direct effect on central sensitization via the microglia cells (see Figure 2). Rapid responses to inflam­ matory pain have been documented in patients treated with these biological agents although randomized controlled trials have so far failed to confirm these encouraging results in a less inflammatory condition – sciatica [37,38] . A novel target for developing analgesics is the capsaicin receptor formally known as tran­ sient receptor potential cation channel subfam­ ily V member 1 (TRPV1). TRPV1 antagonists have shown efficacy in reducing inflammatory

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Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain  and neuropathic pain in rodent studies [39,40] . However, recently it has emerged that TRPV1 is essential in body temperature maintenance and some trials with TRPV1 antagonists had to be stopped because the participants developed undesirable hyperthermia [41] . NGF exerts a modulatory role on nociceptive nerves during adulthood that appears to correlate with hyperalgesic phenomena occurring in tis­ sue inflammation. The high-affinity NGF recep­ tor, trkA, is selectively expressed by nociceptive sensory neurons particularly those containing sensory neuropeptides such as substance P and CGRP. In a number of animal models, much of the hyperalgesia associated with experimen­ tal inflammation is blocked by pharmacological ‘antagonism’ of NGF [42] . Tanezumab, a humanized monoclonal anti­ body that binds and inhibits NGF, was effective in reducing joint pain and improving function in patients with knee OA in a Phase II proof of concept study. However, reports of progressively worsening OA with radiographic evidence of bone necrosis necessitating joint replacement in 16 out of 440 patients led the Phase III trial to be halted by the FDA. The main reason for the instances of joint failure has been presumed to be excess wear and tear on the joint when pain is absent, although a neuropeptide-mediated vascular effect has not been ruled out [43] . Adenosine is an endogenous modulator of pain transmission especially at the spinal cord level. Some preclinical studies have shown that adenosine receptor agonists have antinociceptive effects. There is considerable interest in devel­ oping adenosine agonists and adenosine kinase Bibliography


Papers of special note have been highlighted as: of interest of considerable interest n

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inhibitors as novel analgesic and anti-inflam­ matory agents. Two ectonucleotidases that generate adenosine in nociceptive neurons were also recently identified raising the possibility of treating chronic pain in humans [44] . Following the discovery of defects in the gene of the NaV1.7 sodium channel in conditions such as erythromelalgia and congenital insensi­ tivity to pain, much work is exploring the role of agents that can abrogate nociceptor fiber trans­ mission by interfering with this channel. This has yet to be translated [45] . This is an exciting time to be managing patients with chronic musculoskeletal pain with real advances in the pharmacological manage­ ment that demonstrate clear and meaningful improvements for patients’ pain and function­ ing. The real challenge is to understand the cen­ tral sensitization processes in sufficient detail to be able to manipulate beneficently. Despite this, pharmacological agents will work most effec­ tively for patients with chronic musculoskeletal disease when embedded within a holistic assess­ ment and management plan that should include self-efficacy strategies, physical rehabilitation and appropriate psychological support [46] . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. LeResche L. Epidemiologic perspectives on sex differences in pain. In: Sex, Gender and Pain. Progress in Pain Research and Management (Volume 17). Fillingim RB (Ed.). IASP Press, WA, USA, 233–249 (2004).


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Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain.

SUMMARY Chronic musculoskeletal pain, defined as pain lasting beyond the usual healing time of 6 weeks to 3 months, is a very common condition. It adv...
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