Pregabalin and gabapentin for pain
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1315 (Published 28 April 2020) Cite this as: BMJ 2020;369:m1315
- Stephanie Mathieson, research fellow1 2,
- Chung-Wei Christine Lin, professor1 2,
- Martin Underwood, professor3 4,
- Sam Eldabe, professor5
- 1Institute for Musculoskeletal Health, Sydney, Australia
- 2Sydney School of Public Health, University of Sydney, Australia
- 3Warwick Clinical Trials Unit, University of Warwick, Coventry, UK
- 4University Hospitals Coventry and Warwickshire, Coventry, UK
- 5James Cook University Hospital, Middlesbrough, UK
- Correspondence to S Mathieson stephanie.mathieson{at}sydney.edu.au
What you need to know
Pregabalin and gabapentin can be effective as first line treatment for some people with neuropathic pain such as post-herpetic neuralgia and diabetic peripheral neuropathy
They are not effective for low back pain, sciatica, spinal stenosis, or episodic migraine, and their off-label use for these conditions is not advised
Ask patients to report side effects such as dizziness, sleepiness, and gait problems, which may require the drugs to be tapered and stopped
A 65 year old woman presents with continuous dull back ache and leg pain over the past four years. She underwent lumbar decompression surgery three months ago, but the pain persists. She has no neurological deficits. She is on treatment for hypertension and chronic kidney disease and cannot take non-steroidal anti-inflammatory drugs. She has tried paracetamol, codeine, tramadol, and amitriptyline for her pain in the past with little benefit. You offer a trial of pregabalin and ask her to follow up if she feels dizzy or is not able to tolerate the drug.
What are pregabalin and gabapentin?
Pregabalin and gabapentin, collectively gabapentinoids, are primarily anticonvulsant drugs. Over the past decade, they have been increasingly prescribed for pain.1 They are recommended for neuropathic pain in adults23 (table 1), but are commonly used off-label for other pain disorders such as low back pain, sciatica, and migraine.910 Pregabalin was one of the highest selling drugs globally in 2017.11 In 2018, more than 14 million prescriptions of pregabalin and gabapentin were issued in England.12 This increase in gabapentinoid prescribing may be driven by a desire to avoid opioid analgesics.13
Approved indications for pregabalin and gabapentin
Pregabalin and gabapentin were reclassified as Class C drugs in the UK in April 2019 following an increase in the number of deaths caused by gabapentinoid misuse and addiction.14 Under the UK’s Misuse of Drugs Act, unlawful possession, production, or supply of these drugs is subject to potential punishments and fines. The US Food and Drug Administration has expressed concern over the increasing use of gabapentinoids, mainly when prescribed concurrently with opioid analgesics or benzodiazepines.1 Others have called to have both drugs classified as a Schedule V controlled substance,15 the same class as opioids, to regulate their prescription.
Gabapentinoids bind to the α 2-delta subunit of voltage gated calcium channels, which decreases the release of glutamate, noradrenaline (norepinephrine), and substance P.78 This is believed to contribute to their anticonvulsant, analgesic, and anxiolytic actions.
Search strategy
We searched PubMed (NLM database) and the Cochrane Library with the terms “pregabalin,” “Lyrica,” “gabapentin,” and “Neurontin” for systematic reviews published from 2008 to March 2019 on the benefits, harms, and cost effectiveness of pregabalin and gabapentin. Additionally, we reviewed our personal archives of references and consulted other experts where no reviews were found (eg, information on regulatory changes)
How well do they work?
Neuropathic pain
Moderate quality evidence supports the use of gabapentinoids to improve pain in those with post-herpetic neuralgia or diabetic peripheral neuropathy compared with placebo, as in Cochrane reviews. Nearly four out of 10 people taking pregabalin (600 mg/day) and three out of 10 people taking gabapentin (≥1200 mg/day) for eight weeks or longer achieve at least 50% pain relief.1617 Pain was reduced by one third for 50% of the participants1617 (table 2, fig 1, fig 2). Evidence for other types of neuropathic pain is limited.16
Summary of number needed to treat (NNT) and number need to harm (NNH) for gabapentinoids compared with placebo from systematic reviews of randomised trials
(Top panel) 41 in 100 people with moderate to severe post-herpetic neuralgia or diabetic peripheral neuropathy will have at least 50% pain relief when taking pregabalin at 600 mg/day for eight weeks or longer after initial titration compared with 15 in 100 people taking placebo (moderate quality evidence)16 for post-herpetic neuralgia and 28 in 100 people taking placebo for diabetic peripheral neuropathy (moderate quality evidence).16
(Lower panel) Proportion of people with moderate to severe neuropathic pain taking pregabalin (600 mg/day) who will experience at least one adverse event (69 of 100 people compared with 57 of 100 people taking placebo) (moderate quality evidence), serious adverse event (3.4 of 100 people compared with 3.4 of 100 people taking placebo) (high quality evidence), and misuse of pregabalin (0.5%)16
(Top panel) 32 in 100 people with moderate to severe post-herpetic neuralgia will have at least 50% pain relief when taking gabapentin at ≥1200 mg/day for eight weeks or longer after initial titration compared with 17 in 100 people taking placebo (moderate quality evidence)17
(Middle panel) 38 in 100 people with moderate to severe diabetic peripheral neuropathy will have at least 50% pain relief when taking gabapentin at ≥1200 mg/day for eight weeks or longer after initial titration compared with 21 in 100 people taking placebo (moderate quality evidence)17
(Lower panel) Proportion of people with chronic neuropathic pain taking gabapentin (≥1200 mg/day) who will experience at least one adverse event (63 of 100 people compared with 49 of 100 people taking placebo) (moderate quality evidence), serious adverse event (3.2 of 100 people compared with 2.8 of 100 people taking placebo) (moderate quality evidence) and misuse gabapentin (1.1%)17
Another systematic review of pharmacotherapy for neuropathic pain reports similar effects with gabapentinoids.2 However, the pooling of treatment effects across all drug dosages may have overestimated the treatment effect, particularly with variations in study quality.
Table 2 lists findings from reviews on effects of gabapentinoids on pain relief and the likelihood of harms.
Fibromyalgia
One in 10 patients with moderate to severe fibromyalgia taking pregabalin (300-600 mg daily) experiences a 30-50% reduction in pain over 12 to 26 weeks, based on high quality evidence from a Cochrane review.18 The evidence for gabapentin in fibromyalgia is unclear because of the small number of trials and very low quality of evidence available.19
Other conditions
Systematic reviews have found no treatment benefits of gabapentinoids over placebo in low back pain, sciatica, and spinal stenosis9 or episodic migraine in adults.10 Evidence to support the use of pregabalin in acute pain, HIV neuropathy, neuropathic cancer pain, and other forms of neuropathic pain, is insufficient.16
How do they compare with other treatments for neuropathic pain?
Tricyclic antidepressants (number needed to treat 3.6, 95% confidence interval 3.0 to 4.4; moderate quality evidence) and serotonin-noradrenaline reuptake inhibitors (NNT 6.4, 95% CI 5.2 to 8.4; high quality evidence) are other first line drugs for neuropathic pain. They have smaller NNTs than gabapentinoids and are likely to be more effective.2 The evidence on other anticonvulsant drugs such as carbamazepine, lacosamide, and lamotrigine for neuropathic pain is inconclusive.2
How safe are they?
Adverse events are common and frequently result in discontinuation of the drug. Nearly two in three patients taking these drugs for neuropathic pain experience an adverse event1617 (fig 1, 2).
Adverse events
Dizziness (19%), somnolence (14%), and gait disturbance (14%) are commonly reported with gabapentin, based on moderate quality evidence from a Cochrane review.17 More participants on gabapentin (11%) withdrew from studies because of adverse events compared with placebo (8.2%).17
Dizziness (24%) and somnolence (17%) are also more frequent with pregabalin compared with placebo (6% and 5%, respectively).16 Ninety one per cent of participants taking pregabalin (600 mg/day) for fibromyalgia experienced one or more adverse events compared with 73% in the placebo group as in a Cochrane review (three studies, 1122 participants).18 More participants with fibromyalgia taking pregabalin (28%) withdrew from the studies because of experiencing adverse events compared with placebo (11%).18
Although serious adverse event rates for gabapentinoids are similar to those of placebo in systematic reviews,1617 population based studies show the potential for serious harms. An Australian study found a 57.8% (95% CI 30.0% to 91.6%) yearly increase in intentional poisoning and pregabalin related deaths between 2012 and 2017, corresponding with increased pregabalin prescriptions.20 Opioids, benzodiazepines, and illicit drugs were commonly taken together in those who overdosed on pregabalin.20 Co-prescription of opioid analgesics can increase the risk of opioid related overdose and death (odds ratio 1.49, 95% CI 1.18 to 1.88).21
Potential for misuse
There are 11 940 reports of gabapentinoid misuse and dependence from 2004 to 2015 in an international adverse event database, with more than 75% reported since 2012. A survey of 1500 respondents aged 16-59 in the UK found the self-reported lifetime prevalence of gabapentin and pregabalin misuse was 1.1% and 0.5%, respectively.22 Misuse was defined as any intentional therapeutic use of a drug in an inappropriate way—ie, aside from prescribed doses.22 Gabapentinoid misuse was higher in people with opioid use disorders: 3-68% with pregabalin and 15-22% with gabapentin.22 These values may be an underestimate because of the retrospective nature of included studies. Opioid users tend to select gabapentinoids to boost a euphoric high and reduce withdrawal symptoms while producing only a few adverse effects.14
How are they given and monitored?
Given the risk of adverse events and potential for misuse, caution is advised in prescribing these drugs. Discuss with patients the expected side effects and likely pain relief before prescribing. Australian, British, and Canadian guidelines all recommend gabapentinoids as first line treatment for neuropathic pain. They similarly recommend amitriptyline and duloxetine (Australia and Britain) or serotonin-noradrenaline (norepinephrine) reuptake inhibitors (Canada).32324 Use of these drugs for non-neuropathic pain is not advised. No evidence is available for combination pharmacotherapy.
In practice, a trial of the drug for six to eight weeks may be needed to find out if the benefits justify the potential harms. Review the patient’s ongoing medications. Drug interactions are uncommon as in manufacturers’ information, but co-prescribing with opioids can increase the risk for harms. Manufacturer’s advice is to assess for suicidal behaviour and ideation. Exercise caution when prescribing gabapentinoids for patients with a known history or potential for drug misuse or dependence. Contraindications include known hypersensitivity to these drugs and reduced renal clearance.
Refer to local formulary for appropriate dosing and indications. Manufacturer recommendations for gabapentinoids suggest titration upward for three to seven days in divided doses, to pain relief or a maximum of 600 mg/day for pregabalin in two daily doses7 and up to 3600 mg/day for gabapentin in three daily doses.8
Follow up patients to evaluate response to treatment and any adverse events. Consider stopping if there is no improvement in pain or the patient experiences adverse events which interfere with their work and impair quality of life. The drug should be gradually tapered.1 Abrupt discontinuation may lead to withdrawal effects such as agitation, dysphoria, and fatigue.25 Reducing the dose by 50 to 100 mg/day each week for pregabalin and a maximum 300 mg/day each week for gabapentin is likely to be safe.26
How cost effective are they?
Pregabalin and gabapentin are considered to be of low to moderate price compared with other oral drugs.2 Few studies on their cost effectiveness have been published. One industry sponsored study reported that pregabalin was cost effective for refractory neuropathic pain of mixed causes compared with other analgesics such as opioids and non-steroidal anti-inflammatories.27 Another observational study reported lower healthcare costs when prescribing pregabalin for peripheral neuropathic pain compared with gabapentin.28
Tips for patients
Pregabalin and gabapentin are effective for some types of nerve related pain, such as following shingles or with diabetes. Your doctor may discuss starting these medicines if you have such pain
About 40% of patients with post-herpetic neuralgia or diabetic peripheral neuropathy find at least a 50% improvement in pain with these drugs when taken daily for eight weeks or longer
You may need to take these drugs for eight weeks before you experience improvement in pain
These drugs are not effective for pain relief other than in these conditions and their use is not advised
Consult your doctor before starting these drugs so they can assess your medications and illness history before prescribing
Nearly two in three patients experience side effects such as dizziness, drowsiness, peripheral oedema, and gait disturbance when taking these drugs
Report to your doctor if you experience any adverse effects so they can advise regarding modifying the treatment. Do not abruptly stop the drug
If you are already taking an opioid drug for your pain, taking gabapentin or pregabalin is not recommended. The risk of death is increased if you take both of these drugs. If you are already taking both these drugs, talk to your doctor about tapering and stopping one or both of them
Education into practice
In which situations would you consider prescribing gabapentinoids for pain relief?
Based on reading this article, how would you discuss with a patient the potential pain relief they can expect with gabapentinoids and the risk of adverse events?
What would you advise a patient when starting these drugs?
How patients were involved in the creation of this article
We sought views of patients continuing on gabapentinoids for chronic pain as well those who actively tapered gabapentinoids at the James Cook University Hospital pain clinic, UK. A few patients commented that regular review of medications is helpful to balance pain relief against side effects and manage the appropriate dose. If the medication is not providing pain relief, doctors must advise how to stop it. A patient who stopped pregabalin for low back pain after five years commented, “It has taken me three weeks to completely come off pregabalin and I feel much better for it. My back pain hasn’t changed much but I’m less drowsy and more able to do my job.” Another patient came off gabapentin for sciatica with help from their doctor after three years. Based on their feedback we have highlighted the adverse effects of these drugs and added information on prescribing these drugs and follow-up.
Footnotes
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary’s University, London. To suggest a topic, please email us at practice@bmj.com
Competing interests: No funding was received to conduct this review.
The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests:
SM holds a National Health and Medical Research Council of Australia (NHMRC) Health Professional Research Early Career Fellowship (APP1158463). SM and CL conducted an investigator initiated NHMRC funded trial (PRECISE) published in NEJM in 2017, for which Pfizer Australia provided investigational product only. SE is CI and PI of National Institute for Health Research studies as well as industry sponsored studies. He is chair of the Specialised Pain Clinical Reference Group at NHS England. SE prescribes gabapentinoids as part of his clinical practice. Neither he nor his institution have received funding from the pharmaceutical industry in relation to this or any other work. He consults for manufacturers of neuromodulation devices including Medtronic, Saluda Medical, and Mainstay Medical. SE and MU are co-chief investigator and co-investigator on a UK National Institute for Health Research (NIHR) funded trial of opioid withdrawal ISRCTN49470934. MU is chief investigator or co-investigator on multiple previous and current research grants from the UK NIHR, Arthritis Research UK, and is a co-investigator on grants funded by the Australian NHMRC. 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, which provides electronic data collection for health services research. He is part of an academic partnership with Serco Ltd related to return to work initiatives. He is a co-investigator on two NIHR funded studies that receive additional support from Stryker Ltd. He has accepted honorariums for teaching/lecturing from a consortium for advanced research training in Africa. He was an editor of the NIHR journal series, and a member of the NIHR Journal Editors Group, for which he received a fee.
Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests
Patient consent: The case in this article was fictious and therefore no consent was needed.
Provenance and peer review: commissioned; externally peer reviewed.
Contribution statement and guarantor: article was conceived by CL, planning conducted by SM, and all authors contributed to the proposal and manuscript.