Clinical Notes : Pharmacology

181. Acute and Chronic Musculoskeletal Pain

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Musculoskeletal pain (1)

  • Musculoskeletal pain is common and has significant consequences for affected patients and society as a whole.


  • Musculoskeletal pain is not purely nociceptive; peripheral inflammation and central sensitisation processes, as well as neuropathic components, contribute.


  • Management of patients with these conditions should be multimodal and multidisciplinary, not rely on pharmacological approaches alone, and follow principles of chronic disease management aiming for improved function. Consider adjunct :

    • Pysiotherapy

    • Occupational therapy

    • Pain management psychology

  • Nonopioid analgesics, in particular NSAIDs, play an important role in the pharmacological management of patients with these conditions.


  • Opioids should be used with caution and only after careful consideration in patients with musculoskeletal pain; tramadol, buprenorphine and tapentadol may be preferable.


  • Adjuvants such as anticonvulsants (e.g. pregabalin) and antidepressants (e.g. duloxetine) may play a previously underestimated role in the management of patients with musculoskeletal pain

Musculoskeletal pain is :


  • a major burden on the psychosocial and physical wellbeing of an individual.(2)


  • one of the most common chronic in the primary care setting.(3)


  • caused by conditions of the bones, muscles and their attachments (i.e. tendons, ligaments and connective tissues), and arthritis (i.e. joints).(4)


  • ranges in time frame from sudden-onset and short-lived problems to life-long chronic disorders.


  • common in the elderly with significant comorbidities and increased risk of adverse effects of medications. Clinical assessment and investigations for underlying medical disease or chronic inflammatory conditions should be performed to avoid missing other diagnoses or stereotyping patients.(5)


Common approaches to managing patients with musculoskeletal pain include pharmacotherapy

  • surgery

  • injections

  • physical therapy

  • psychological approaches such as hypnosis, relaxation and cognitive behavioural therapy

  • complementary or alternative medicines

Mechanisms of pain


Early concepts focused on degenerative wear and tear of the musculoskeletal elements as the main underlying mechanism of musculoskeletal pain, with inflammatory factors leading to peripheral sensitisation. However, more recent data suggest that central sensitisation and, in particular, neuropathic elements also play a significant role in the background of musculoskeletal pain.(6)


In the joint :

  • peripheral unremitting infammatory reactions cause peripheral sensitisation, especially after an acute injury

  • different types of mechano-receptors cause local sensitisation.(7)  

  • subsequent central neuronal plasticity causes perpetuation of pain, commonly called central sensitisation.(8)


In the central nervous system :

  • central sensitisation is caused by signal amplification that augments pain perception leading to allodynia (non-noxious stimuli perceived as pain) and hyperalgesia (heightened response to painful stimuli).

  • clinically, patients with dominant features of central sensitisation experience disproportionate pain, fatigue, cognitive impairment and other somatic symptoms such as sleep deprivation, stress and anxiety.




A. Nonopioid analgesics


1. Paracetamol


  • has no specific endogenous binding sites, hence the continuous debates surrounding its mechanisms of action.(9)


  • is an effective analgesic acute post-operative pain (10)


  • is not as effective in musculoskeletal pain conditions (11) (12)


  • combined with an NSAID is superior to either compound alone (13) (14)


  • combined with a weak opioid such as codeine or tramadol is more effective than paracetamol on its own (15)

Paracetamol recommended dose ::500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

  • paracetamol / ibuprofen combined recommended dose : 500mg / 150mg One or two tabs every six hourly

  • paracetamol / codeine combined recommended dose : 500mg /  15 or 30mg. One or two tabs every six hours.

  • paracetamol / tramadol combined recommended dose : 325 / 37,5mg One or two tabs every six hours


An approach to long-term therapy for musculoskeletal pain (16)

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2. Systemic NSAIDs

Advantages :

  • represent a sensible strategy for treating patients with acute and chronic musculoskeletal pain. (16) (17)


  • have an established analgesic efficacy in the treatment of :

    • acute postoperative pain.(22)

    • chronic low back pain and acute ankle sprain.(18)

    • In OA, NSAIDs provide clinically meaningful analgesia superior to paracetamol and comparable with opioids.(12) (19)


  • risks of falls, fractures and hospital admissions were lower with nsNSAID and COX-2 inhibitor use than with opioid use.(20)


There seems to be no difference in efficacy between appropriate doses of nonselective NSAIDs (nsNSAIDs) and the selective NSAIDs, cyclo-oxygenase (COX)-2 inhibitors.(21)

ibuprofen recommended dose : 300-400 mg orally every 6-8 hours when required, maximum 2400 mg/day

naproxen recommended dose : 250-500 mg orally twice daily when required, maximum 1250 mg/day

diclofenac sodium recommended dose : 100 mg orally (extended-release) once daily when required

celecoxib recommended dose : 100-200 mg orally twice daily when required

Disadvantages :


The main concerns with short- and long-term use of nsNSAIDs are (21) :


  • upper and lower gastrointestinal (GI) events (i.e. ulceration, bleeding, perforation or NSAID enteropathy)

    • Upper GI events due to nsNSAIDs are relatively reduced when combined with proton pump inhibitors (PPI) in susceptible patients, but PPIs are not protective for NSAID enteropathy.(16)

    • COX-2 inhibitors show reduced GI adverse effects compared with nsNSAIDs.(22 )

    • The best gastro-protective combination in high-risk patients who had previous GI bleeding is a COX-2 inhibitor plus a PPI.(23)


  • risks of cardiovascular (CV) events

    • naproxen is associated with less harm from CV events compared with other nsNSAIDs.(24)

    • celecoxib has a similar rate of CV effects (22)


  • renal impairment

    • less risk from COX-2 inhibitors (25)



3. Topical NSAIDs


  • Topical NSAIDs are effective for the treatment of patients with short-term exacerbation or acute attacks of localised pain, such as strains, sprains or sports injuries, which often occur in the setting of chronic musculoskeletal pain.


  • Application of a topical gel of ketoprofen, ibuprofen, diclofenac and piroxicam, but not indomethacin, two to three times daily provides effective pain relief with systemic adverse effects comparable with placebo.(26 )


  • Topical diclofenac and ketoprofen can provide pain relief in individuals with chronic pain due to OA with adverse effects comparable with placebo.(27)


  • Topical rubefacients containing salicylates seem not to be effective in people with acute and chronic conditions.(28)



B. Opioids


Chronic opioid therapy should be utilised only with great caution and when all other safer alternatives have not been effective or not suitable.(29)

No evidence was found that con-tinuous administration of controlled-release opioids is more effective or safer than inter-mittent use of immediate-release opioids or reduces opioid misuse or addiction.(30)


The atypical opioids (tramadol, tapentadol and transdermal buprenorphine) offer some advantages in the chronic pain setting.


C. Antidepressants


1. Duloxetine


Duloxetine is :


  • a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant, which has been extensively studied for use in patients with neuropathic pain regardless of its disease origin and is recommended as a first-line treatment diabetic peripheral neuro-pathic pain and chronic musculoskeletal pain.(31)


  • effective compared with placebo in chronic knee OA and chronic low back pain, with significant improvement in physical outcomes.(32) (33)


Observed adverse effects of duloxetine are nausea, fatigue and constipation.(34) (68)

Duloxetine recommended dose : 30-60 mg orally once daily

2. Other antidepressants


Other SNRIs such as venlafaxine and tricyclic antidepressants (TCAs) such as amitriptyline may be useful in managing patients with neuropathic pain (off-label uses), but there are no studies to support their use in patients with musculoskeletal pain.

TCAs are best avoided in the elderly because their anticholinergic activity increases the cumulative risk of cognitive impairment and mortality in this age group.(35)



D. Anticonvulsants


1. Gabapentin and pregabalin

  • recommended as first-line treatment for patients with neuropathic pain.(31)


  • effective in treating patients with fibromyalgia (off-label uses).(36)


  • In OA, pregabalin was found to be as effective as meloxicam and the combination of both (37)

Gabapentin recommended dose : 300 mg orally once daily on day one, followed by 300 mg twice daily on day 2, followed by 300 mg three times daily on day 3, then titrate dose slowly according to response, maximum 3600 mg/day

Pregabalin Recommended dose : 75-150 mg orally twice daily, maximum 300 mg/day

E. Muscle relaxants

Patients with severe myofascial pain who do not respond to physiotherapy may also benefit from additional use of a muscle relaxant such as tizanidine.(38)

Tizanidine recommended dose : 1-2 mg orally once daily at bedtime initially, increase gradually according to response, maximum 24 mg/day given in 2-3 divided doses

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1. Schug SA, Arshad AAM

Musculoskeletal Pain - Pharmacological Management

MedicineToday : Conventional and Atypical Opioids Supplement September 2018


2. Australian Institute of Health and Welfare (AIHW). Arthritis, osteoporosis and other musculoskeletal conditions.

Canberra: AIHW; 2015.

3. Patel DR, Moore MD, Greydanus DE.

Musculo-skeletal diagnosis in adolescents.

Adolesc Med StateArt Rev 2007; 18: 1-10, vii.


4. European league Against Rheumatism (EUlAR).

Musculoskeletal Health in Europe.

Reportv5.0. Brussels: EUlAR; 2015.


5. Niemeyer lO.

Social labeling, stereotyping, and observer bias in workers’ compensation: the impact of provider-patient interaction on outcome.

J Occup Rehabil 1991; 1: 251-269.


6. Dimitroulas T, Duarte RV, Behura A, Kitas GD, Raphael JH.

Neuropathic pain in osteoarthritis: a review of pathophysiological mechanisms and implications for treatment.

Semin Arthritis Rheum 2014; 44: 145-154.


7. Perrot S.

Targeting pain or osteoarthritis? Implications for optimal management of osteoarthritis pain.

IASP Pain Clinical Updates2016; XXIV: No 2.


8. Woolf CJ.

Central sensitization: uncovering the relation between pain and plasticity.

Anesthesiology2007; 106: 864-867.


9. Graham GG, Davies MJ, Day RO, MohamudallyA, Scott kF.

The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings.

Inflammopharmacology 2013; 21: 201-232.


10. Moore RA, Derry S, McQuay HJ, Wiffen PJ.

Single dose oral analgesics for acute postoperative pain in adults.

Cochrane Database Syst Rev 2011; (9): CD008659.


11. Williams CM, Maher CG, Latimer J, et al.

Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial.

lancet 2014; 384: 1586-1596.


12. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE,Wong JB, McAlindon TE.

Comparative effectiveness of pharmacologic interventions for knee osteo-arthritis: a systematic review and network meta-analysis.

Ann Intern Med 2015; 162: 46-54.


13. Ong Ck, Seymour RA, Lirk P, Merry AF.

Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain.

Anesth Analg 2010; 110: 1170-1179.


14. Bailey E, Worthington HV, van Wijk A, Yates JM, Coulthard P, Afzal Z.

Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth.

Cochrane Database Syst Rev 2013; (12): CD004624.


15. Schug SA.

Combination analgesia in 2005 - a rational approach: focus on paracetamol-tramadol.

Clin Rheumatol 2006; 25 Suppl 1: S16-21.


16. Scarpignato C, lanas A, Blandizzi C, et al.

Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis – an expert consensusaddressing benefits as well as gastrointestinal and cardiovascular risks.

BMC Med 2015; 13: 55.


17. Berenbaum F.

Osteoarthritis as an inflamma-tory disease (osteoarthritis is not osteoarthrosis!).

Osteoarthritis Cartilage 2013; 21: 16-21.


18. Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J.

APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine.

Acute pain management: scientific evidence, 4th ed. Melbourne: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2015.


19. Smith SR, Deshpande BR, Collins JE, katz JN, losina E.

Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review.

Osteoarthritis Cartilage 2016; 24: 962-972.


20. Solomon DH, Rassen JA, Glynn RJ, lee J, levinR, Schneeweiss S.

The comparative safety of analgesics in older adults with arthritis.

Arch Intern Med 2010; 170: 1968-1976.


21. Labianca R, Sarzi-Puttini P, Zuccaro SM, Cherubino P, Vellucci R, Fornasari D.

Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain.

Clin Drug Investig 2012; 32 Suppl 1: 53-63.


22. Moore RA, Derry S, McQuay HJ.

Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk.

BMC Musculoskelet Disord 2007; 8: 73.


23. Chan Fk, Wong VW, Suen BY, et al.

Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial.

lancet 2007; 369: 1621-1626.


24. Trelle S, Reichenbach S, Wandel S, et al.

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.

BMJ 2011; 342: c7086.


25. Lafrance JP, Miller DR.

Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury.

Pharmacoepidemiol Drug Saf 2009; 18: 923-931.


26. Massey T, Derry S, Moore RA, McQuay HJ.

Topical NSAIDs for acute pain in adults.

Cochrane Database Syst Rev 2010; (6): CD007402.


27. Derry S, Conaghan P, Da Silva JA, Wiffen PJ, Moore RA.

Topical NSAIDs for chronic musculoskeletal pain in adults.

Cochrane DatabaseSyst Rev 2016; (4): CD007400.


28. Derry S, Matthews PR, Wiffen PJ, Moore RA.

Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults.

Cochrane Database Syst Rev 2014; (11): CD007403.


29. Royal Australian College of General Practitioner (RACGP).

Guidelines for the non-surgical management of hip and knee arthritis.

Melbourne: RACGP; 2009.


30. Centers For Disease Control and Prevention Public Health Service US Department of Health and Human Services.

Guideline for prescribing opioids for chronic pain.

J Pain Palliat Care Pharmacother 2016; 30: 138-140.


31. Finnerup NB, Attal N, Haroutounian S, et al.

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

lancet Neurol 2015; 14: 162-173.


32. Chappell AS, Ossanna MJ, liu-Seifert H, et al.

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

Pain 2009; 146: 253-260.


33. Skljarevski V, Desaiah D, liu-Seifert H, et al.

Efficacy and safety of duloxetine in patients with chronic low back pain.

Spine 2010; 35: E578-E585.


34. Citrome l, Weiss-Citrome A.

Antidepressants and the relief of osteoarthritic pain – findings from a study examining adjunctive duloxetine.

Int J Clin Pract 2012; 66: 431-433.


35. Fox C, Richardson K, Maidment ID, et al.

Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study.

J Am Geriatr Soc 2011; 59: 1477-1483.


36. Uceyler N, Sommer C, Walitt B, Hauser W.

Anticonvulsants for fibromyalgia.

Cochrane Database Syst Rev 2013; (10): CD010782.


37. Ohtori S, Inoue G, Orita S, et al.

Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis.

Yonsei Med J 2013; 54: 1253-1258.


38. Chronic Pain Syndromes

BMJ Best Practice

Last reviewed:September 2019

Last updated:July  2018


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The following meds are available in Ireland :


Paracetamol 500 / ibuprofen 150 (Eeasolief duo)

Paracetamol 500 / codeine 15 (Codipar)

Paracetamol 500 / codeine 30 (Kapake, Tylex, Solpadol)

Paracetamol 325 / tramadol 37,5 (Xymel comp, Ixprim, Ixprim Effervescent)


Tramadol (Tradol, Tramadol HCL, Tramake, Tramapine, Xymel, Zydol)

Tapentadol (Palexia)

Transdermal Buprenorphine (Butrans, Transtec)


Naproxen (Naprosyn)

Naproxen/esomeprasole (Vimovo)

Celecoxib (Celebrex)


Duloxetine (Cymbalta, Duloxetine Clonmel, Duloxetine Rowa,Yentreve)

Venlafaxine (Efexor XL, Ireven, Vedixal, Vedixal XL, Venex XL, Venlafgaxine Teva, Venlofex)


Gabapentin (Gabin, Neurontin, Neurostil)

Pregabalin (Lyrica, Pregabalin Clonmel, Pregabalin Sandoz)


Tizanidine : (Zanaflex, Tizanidine INN)


Ketoprofen gel (Fastum gel, Oruvail gel)

Ibuprofen gel (Ibugel, Nurofen gel, Phorpain gel)

Diclofenac gel (Voltarol gel, Diclofenac spray gel, Diclac gel)

The following meds are not available in Ireland :


Piroxicam gel


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