REVIEW For reprint orders, please contact: [email protected]
Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain
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  .
Chronic musculoskeletal pain is maladaptive and is defined as pain that lasts beyond the healing time, usually 30% reduc tion in pain was five  . 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 (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  . 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  . 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
future science group
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  . 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  . 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  . 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
Woolf CJ; American College of Physicians, American Physiological Society. Pain: moving from symptom control toward mechanismspecific pharmacologic management. Ann. Intern. Med. 140, 441 (2004). Review of the pathophysiology underlying the pharmacological management of pain. Bonica JJ. The management of pain. In: Bonica’s Management of Pain (2nd Edition). Lea and Febiger, PA, USA (1990). Crombie IK, Croft PR, Linton SJ, LeResche L, Von Korff M. Epidemiology of Pain. IASP Press, WA, USA (1999).
future science group
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  . 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  . 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  . 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).
Melzack R, Wall PD. Pain mechanisms: a new theory. Science 150(699), 971–979 (1965). Melzack and Wall introduced their ‘gate control’ theory in this seminal article offering a physiological explanation for pain modulation.
Maniadakis A, Gray A. The economic burden of back pain in the UK. Pain 84, 95–103 (2000).
Waddell G, Burton K, Kendall N. Vocational Rehabilitation – What Works, For Whom and When? TSO, London, UK (2008).
Bhave G, Gereau RW. Posttranslational mechanisms of peripheral sensitization. J. Neurobiol. 61(1), 88–106 (2004).
McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract. Res. Clin. Rheumatol. 21(3), 403–425 (2007) .
Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 152(Suppl. 3), S2–S15 (2010).
Detailed description of epidemiological aspects of chronic musculoskeletal pain. Linton SJ. A review of psychological risk factors in back and neck pain. Spine 25(9), 1148–1156 (2000).
Recent article describing the current understanding of the role of central sensitization in pain.
12 Dieppe P. Developments in osteoarthritis.
Rheumatology 50(2), 245–247 (2011).
Review Kuttikat & Shenker 13 Bajaj P, Graven-Nielsen T, Arendt-Nielsen L.
27 Carville SF, Arendt-Nielsen S, Bliddal H et al.
Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study. Pain 93, 107–114 (2001).
EULAR evidence based recommendations for the management of fibromyalgia syndrome. Ann Rheum. Dis. 67, 536–541 (2008).
Dickenson AH. Spinal cord pharmacology of pain. Br. J. Anaesth. 75(2), 193–200 (1995)
Dubner R, Hargreaves KM. The neurobiology of pain and its modulation. Clin. J. Pain. 5 (2), S1–S4; discussion S4–S6 (1989).
Buskila D. Genetics of chronic pain states. Best Pract. Res. Clin. Rheumatol. 21(3), 535–547 (2007). Holliday J, Neogi KL, Felson T et al. Neurotransmitter receptor gene polymorphisms are associated with widespread pain: findings from the first genome-wide association study of musculoskeletal pain. Arthritis Rheum. 62(Suppl. 10), 836 (2010). Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 63, 901–907 (2004). Wolfe F, Zhao S, Lane N. Preference for nonsteroidal anti-inflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Arthritis Rheum. 43(2), 378–385 (2000).
Crofford LJ. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat. Rev. Rheumatol. 6(4), 191–197 (2010).
29 Bardin L, Gregoire S, Aliaga M et al.
Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of stress-induced ultrasonic vocalizations in rats. Neurosci. Res. 66, 135–140 (2010). duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents. J. Pharmacol. Exp. Ther. 312, 726–732 (2005). 31
A randomized, double-blind, placebocontrolled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119(1–3), 5–15 (2005). n
et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo controlled trial. Pain 146, 253–260 (2009). 34 Crofford LJ, Rowbotham MC, Mease PJ et al.
Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 52, 1264–1273 (2005). n
25 Goldenberg DL. Pharmacologic treatment of
Management of fibromyalgia syndrome. JAMA 292, 2388–2395 (2004).
38 Leung L, Cahill CM. TNF-a and
neuropathic pain – a review. J. Neuroinflammation 7, 27 (2010). 39 Jhaveri MD, Elmes SJ, Kendall DA,
Chapman V. Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heatevoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats. Eur. J. Neurosci. 22(2), 361–370 (2005).
40 Gunthorpe MJ, Szallasi A. Peripheral TRPV1
receptors as targets for drug development: new molecules and mechanisms. Curr. Pharm. Des. 14(1), 32–41 (2008). 41 Gavva NR, Treanor JJ, Garami A et al.
Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136 (1–2), 202–210 (2008). 42 McMahon S. NGF as a mediator of
inflammatory pain. In: Neurotrophins and Sensory Neurons: Role in Development, Maintenance and Injury. McMahon S (Ed.). Royal Society, London, UK, 431–440 (1996). 43 Lane NE, Schnitzer TJ, Birbara C et al.
Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).
Good quality randomized controlled trial providing evidence for efficacy of duloxetine in fibromyalgia.
33 Chappell AS, Ossanna MJ, Liu-Seifert H
24 Schug SA. The role of tramadol in current
26 Goldenberg DL, Burckhardt C, Crofford L.
Arnold LM, Lu Y, Crofford LJ et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 50, 2974–2984 (2004).
32 Arnold LM, Rosen A, Pritchett YL, et al.
Tramadol for neuropathic pain. Cochrane Database Syst. Rev. 3, CD003726 (2006).
fibromyalgia and other chronic musculoskeletal pain. Best Pract. Res. Clin. Rheumatol. 21, 499–511(2007).
The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3‑month follow-up study. Spine 30(24), 2724–2728 (2005).
30 Jones CK, Peters SC, Shannon HE. Efficacy of
23 Hollingshead J, Dühmke RM, Cornblath DR.
treatment strategies for musculoskeletal pain. Ther. Clin. Risk Manag. 3(5), 717–723 (2007).
37 Korhonen T, Karppinen J, Paimela L, et al.
Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 39, 1852–1859 (1996).
22 Ilett KF, Paech MJ, Page-Sharp M et al. Use of
a sparse sampling study design to assess transfer of tramadol and its O-desmethyl metabolite into transitional breast milk. Br. J. Clin. Pharmacol. 65(5), 661–666 (2008).
oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 60(1), 299–309 (2009).
Guidelines based on current evidence for management of fibromyalgia.
28 Goldenberg D, Mayskiy M, Mossey C,
20 Leith JL, Wilson AW, Donaldson LF,
Lumb BM. Cyclooxygenase-1-derived prostaglandins in the periaqueductal gray differentially control C- versus A-fibre-evoked spinal nociception. J. Neurosci. 27(42), 11296–11305 (2007).
36 Russell IJ, Perkins AT, Michalek JE. Sodium
Good quality randomized controlled trial providing evidence for efficacy of pregabalin in fibromyalgia. Arnold LM, Goldenberg DL, Stanford SB et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 56, 1336–1344 (2007).
Pain Manage. (2011) 1(6)
44 Zylka MJ. Pain-relieving prospects for
adenosine receptors and ectonucleotidases Trends Mol. Med. 17(4), 188–196 (2011). 45
Cox JJ, Reimann F, Nicholas AK et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).
46 Eccleston C, Williams AC, Morley S.
Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst. Rev. 2, CD007407 (2009). 47 Fields HL, Basbaum AI. Central nervous
system mechanisms of pain modulation. In: Textbook of Pain (4th Edition). Wall PD, Melzack R (Eds). Churchill Livingstone, London, UK, 310 (1999). 48 Watkins LR, Maier SF. GLIA: a novel drug
discovery target for clinical pain. Nat. Rev. Drug Discov. 2, 973–985 (2003).
future science group