Drugs for chronic pain

INTRODUCTION

In August 2020, the National Institute for Health and Care Excellence (NICE) published the draft guidance on chronic pain, which perhaps controversially advises against the use of all drugs except antidepressants.¹ The committee cite an absence of evidence on effectiveness, their experience, information in product summaries, and the established or possible risk of harm as justification for their negative recommendations. Public reaction perhaps reflects the assumption the guidelines apply to all chronic pain conditions. This is not the case. The guideline explicitly does not cover pain conditions that have existing NICE guidelines including headache, low back pain (LBP) and irritable bowel syndrome (IBS).^1–6 This creates an interesting tension, since some recommendations are discordant (Box 1).

Box 1.

Concordance between drug recommendations in draft NICE chronic pain guideline and NICE guidelines for low back pain, headache, irritable bowel syndrome, and osteoarthritis

Drug class	Draft NICE guideline: chronic pain in over 16s, August 20201	NICE guideline: low back pain and sciatica in over 16s, updated September 20205	NICE guideline: headache in over 12s, updated November 20154,a	NICE guideline: irritable bowel syndrome in adults, updated April 20176	NICE guideline: osteoarthritis, updated February 20148
Opioids	Do not offer	Do not offer	Be alert to the possibility of medication overuse headache in people whose headache developed or worsened while they were taking the following drugs for ≥3 months: opioids, on 10 days per month or more; or paracetamol, aspirin, or an NSAID, either alone or in any combination, on 15 days per month or more	No specific recommendation	If paracetamol or topical NSAIDs are insufficient consider the addition of opioid analgesics
NSAIDs	Do not offer	Consider oral NSAIDs (conditions apply)		No specific recommendation	Where paracetamol or topical NSAIDs are ineffective consider substitution with (or addition of) an oral NSAID/COX-2 inhibitor
Paracetamol (acetaminophen)	Do not offer	Do not offer paracetamol alone		No specific recommendation	Consider offering paracetamol in addition to core treatments.
Antidepressants	Consider an antidepressant, either duloxetine, fluoxetine, paroxetine, citalopram, sertraline, or amitriptyline	Do not offer SSRIs, serotonin–norepinephrine reuptake inhibitors, or tricyclic antidepressants	Consider amitriptyline for the prophylactic treatment of migraine	Consider TCAs as second line treatment for people with IBS. Consider SSRIs for people with IBS only if TCAs are ineffective	No specific recommendation
Anticonvulsants	Do not offer	Do not offer	Do not offer gabapentin for prophylactic management of migraine	No specific recommendation	No specific recommendation

^aThe guidance for headache is not specific to chronic headache pain. NSAIDs and paracetamol are recommended for acute treatment of tension headache and migraine with or without aura. IBS = iritable bowel syndrome. NICE = National Institute for Health and Care Excellence. NSAID = non-steroidal anti-inflammatory drug. SSRI = selective serotonin reuptake inhibitor. TCA = tricyclic antidepressants.

SUMMARY

The guideline committee used the International Classification of Diseases, 11th Revision definition of chronic primary pain to define their population:

‘... pain in one or more anatomical regions that (1) persists or recurs for longer than 3 months, (2) is associated with significant emotional distress … and/or significant functional disability … (3) ... the symptoms are not better accounted for by another diagnosis.’ ⁷

Crucially, therefore, the guidance can strictly only be applied to people with emotional distress and/or functional disability. Nevertheless, NICE did not use these criteria to select articles for the evidence review. The recommendations against non-steroidal anti-inflammatory drugs (NSAIDs) are informed by just three trials (two of fibromyalgia, and one of orofacial muscle pain). No studies were identified for paracetamol or opioids and a handful of trials on gabapentinoids. The recommendations for antidepressants come primarily from trials in women with fibromyalgia.³

Unsurprisingly, the NICE guidance against NSAIDs or paracetamol, and the endorsement of antidepressants for chronic pain, has come under scrutiny.¹ The committee did not consider the evidence for harms from NSAIDs or paracetamol and instead focussed on safety of opioids and gabapentinoids.^2,3 In 2014, NICE did look at evidence for paracetamol safety for an osteoarthritis guidance update.⁸ The committee were concerned about observational data linking paracetamol at increasing doses to cardiovascular, gastrointestinal, and renal adverse events.^9,10 Observational data on paracetamol harms should be considered cautiously because of risk of confounding, and typically evaluated persistent use at high therapeutic doses.⁹ A positive recommendation for paracetamol for osteoarthritis remained pending a full review of evidence on the pharmacological management of osteoarthritis. This review is still awaited.

Other NICE guidelines advise against paracetamol for cluster headache or as sole treatment for LBP (Box 1).^4,5 Where there is limited evidence to guide the use of paracetamol for specific conditions (such as IBS), a recommendation was not made. Prescribing rates for paracetamol and co-codamol (paracetamol plus low dose codeine) are unchanged over recent years, with the majority of these prescriptions being for chronic pain.¹¹ In England, there were >15.5 million prescriptions for paracetamol 500 mg tablets.¹² This equates to 1.86 billion tablets, or ∼43 for each adult. Paracetamol is also available over the counter and in supermarkets, with limited opportunity for counselling on judicious use. This may lead to overuse, duplication of therapy, and inadvertent poisonings. In Australia, there were ∼43 paracetamol overdose deaths per year between 2004 and 2017.¹³ Owing to safety concerns, particularly with modified release preparations, there have been policy changes limiting access to certain paracetamol formulations in some countries.¹⁴

Oral NSAIDs also remain popular with ∼11.5 million prescriptions in England in 2018 (26% reduction since 2013).¹² There is a role for oral NSAIDs for certain chronic pain conditions, for example, they provide modest benefit for pain in chronic LBP¹⁵ and are recommended in existing NICE guidelines for LBP.⁵ NSAIDs are discouraged for cluster headache, but recommended for tension headache and migraine with or without aura.⁴ This provides an example of how application of the new guidance depends on the specific pain condition under consideration. However, the adverse events of NSAIDs, particularly in older people, are well known.¹⁶ For many older people getting regular repeat prescriptions for paracetamol, co-codamol, or NSAIDs, the harms may outweigh the benefits.

The NICE guidance against opioid analgesics and gabapentinoids for chronic pain reflects the established risk of harms with both time-limited and persistent use of these drugs.^17,18 There are limited indications for gabapentinoids for specific chronic painful disorders, and while guidelines internationally are inconsistent, existing evidence only supports their use for post-herpetic neuralgia.¹⁸ Furthermore, aside from LBP, antidepressants are consistently recommended for common chronic pain conditions, including headache and IBS.^4,6

CONCLUSION

Weaning the population off paracetamol, NSAIDs, and opioids for chronic non-malignant pain is a major challenge for general practice. It is important clinicians are aware of the indications where this is appropriate. The draft NICE guidance on chronic pain also reviewed the qualitative literature and highlighted the importance of the doctor-patient relationship and shared decision making. They make specific recommendations, for example, about developing care plans and communicating test results. This is the very stuff of general practice. It is over 60 years since Michael Balint wrote The Doctor, His Patient and The Illness.¹⁹ Aside from his antiquated view on doctor gender, it is worth revisiting his ideas. The future GP when managing chronic pain perhaps needs to be more the drug doctor and less the doctor with drugs.

Provenance

Commissioned; externally peer reviewed.

Competing interests

Christina Abdelshaheed and Gustavo C Machado received heat wraps at no cost for the trials they are lead investigators on. Martin Underwood is chief investigator or co-investigator on multiple previous and current research grants from the UK National Institute for Health Research (NIHR), Arthritis Research UK and is a co-investigator on grants funded by the Australian National Health and Medical Research Council. He is an NIHR Senior Investigator. He has received travel expenses for speaking at conferences from the professional organisations hosting the conferences. He is a director and shareholder of Clinvivo Ltd that provides electronic data collection for health services research. He is part of an academic partnership with Serco Ltd, funded by the European Social Fund, related to return to work initiatives. He is a co-investigator on two NIHR funded studies receiving additional support from Stryker Ltd. He has accepted honoraria for teaching/lecturing from consortium for advanced research training in Africa. Until March 2020 he was an editor of the NIHR journal series, and a member of the NIHR Journal Editors Group, for which he received a fee.