NIHR Signal Two nerve drugs are not suitable for treating long-term low back pain

Published on 5 December 2017

The drugs gabapentin and pregabalin (gabapentinoids) were found not to help lower back pain that had lasted more than three months. Gabapentin gave no benefit compared with placebo, while pregabalin was less effective than other painkillers. Both were associated with several side effects, such as dizziness.

Long-term low back pain without clear cause is very common. It causes considerable loss of productivity and places a high demand on the healthcare service. It is difficult to treat, and people often get limited relief from simple painkillers, causing practitioners to consider alternative options.

This review gathered eight trials looking at gabapentinoids for adults with long-term lower back pain. The evidence was very low quality, but overall, supports NICE guidance not to use these drugs to treat long-term lower back pain.

Larger, high-quality studies may provide further insight, particularly regarding their value when there is associated sciatica as gabapentinoids may help some types of nerve pain.

Two nerve drugs are not suitable for treating long-term low back pain

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Why was this study needed?

Lower back pain is a common problem experienced by up to eight out of 10 people in the UK at some point in their lives. It can be very debilitating and affect the ability to carry out daily activities including work. Lower back pain is termed long-term when it has lasted for over three months. Often no clear cause can be found, particularly when there is no sciatica (leg pain suggesting direct pressure on a nerve) and finding a suitable treatment can be difficult.

For long-term low back pain, simple painkillers can be ineffective, and there is a move against prescribing stronger opioid-based pain-relief. Gabapentinoids are a group of antiepileptic drugs for the treatment of nerve pain that have been suggested as options for chronic lower back pain, though the evidence for this use is uncertain.

NHS Digital figures show NHS primary care prescriptions of pregabalin have increased more than ten-fold, from less than half a million in 2006 to just over 5.5 million in 2016. Gabapentin prescriptions have also risen from just over one million to 6.5 million over the same period. The commonest indication for this is neuropathic pain - in line with NICE guidance in 2013 (updated in 2017) which suggests a gabapentinoid as first-line treatment.

It is important to know whether they are effective for long-term lower back pain and whether there are any associated harms.

What did this study do?

This systematic review included eight randomised controlled trials assessing the effects of gabapentinoids in adults with chronic lower back pain.

Three trials compared gabapentin with placebo, three compared pregabalin with other drugs, and two looked at using pregabalin alongside other drugs.

Most studies were small and based in a single centre. None came from the UK. Chronic lower back pain had lasted for between one and 18 years, and treatment duration ranged from three to 14 weeks. Pain relief was measured on numerous scales. Evidence was judged to be low to very low quality for most outcomes.

Though trials of chronic lower back pain with or without leg pain were reportedly eligible, the researchers excluded trials in people with predominant leg pain or nerve compression. Only three trials questioned nerve pain specifically.

What did it find?

  • Gabapentin provided a non-significant improvement in pain compared to placebo. The standardised mean difference (SMD) was 0.22 units (95% confidence interval [CI] -0.5 to +0.07) on a patient-reported scale of 0 to 10, where lower numbers indicate less pain (three studies, 185 participants).
  • Pregabalin was less effective at reducing pain than the other medications. The SMD was 0.42, which is a moderate effect in favour of the other drugs (95% CI 0.20 to 0.64). This was from a meta-analysis of three studies (332 participants), one of which compared pregabalin with an antidepressant class drug (amitriptyline), one a type of anti-inflammatory (celecoxib) and one paracetamol combined with an opioid (Tramacet).
  • There was no benefit when pregabalin was given alongside the opioids tapentadol (SMD -0.04, 95% CI -0.26 to +0.18; one study, 306 participants) or buprenorphrine (SMD -0.42, 95% CI -1.02 to +0.17; one study, 44 participants). There was a small benefit when pregabalin was combined with celecoxib compared with celecoxib alone (SMD -0.81, 95% -1.29 to -0.33; one study, 72 participants).
  • Adverse events were more common with gabapentin and included dizziness (relative risk [RR] 1.99, 95% CI 1.17 to 3.37), fatigue (RR 1.85, 95% CI 1.12 to 3.05), difficulty thinking (RR 3.34, 95% CI 1.54 to 7.25), and visual disturbances (RR 5.72, 95% CI 1.94 to 16.91). People taking pregabalin were more likely to experience dizziness than those taking other active pain relief (RR 2.70, 95% CI 1.25 to 2.70).

What does current guidance say on this issue?

NICE guidelines on low back pain and sciatica in over-16s state that anticonvulsants should not be offered for managing low back pain. Self-management and exercise programmes are core components of care. Non-steroidal anti-inflammatories (NSAIDs) are the recommended drug treatment, with weak opioids (with or without paracetamol) considered only if NSAIDs are contraindicated, not tolerated or ineffective.

However, for management of sciatica NICE refer to their Neuropathic pain guidelines, which do recommend gabapentin or pregabalin as initial treatment options for neuropathic pain.

NICE Key Therapeutic Topic guidance (2017) notes that “The use of both gabapentin and pregabalin can lead to dependence and these medicines may be misused or diverted.”

What are the implications?

There are few effective drug treatments available for people with non-specific chronic lower back pain. There is no evidence at present to suggest that gabapentinoids are effective. Furthermore, the associated adverse events do not seem to justify prescribing them in this group.

This systematic review, in general, supports current NICE guidance on this topic. The grey area, however, is people with associated sciatica. The studies included in this review were not able to differentiate whether they may benefit.

GPs and Clinical Commissioning Groups may want to consider reviewing local usage of gabapentinoids in people with chronic lower back pain.

Citation and Funding

Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: a systematic review and meta-analysis of randomized controlled trials. PLoS Medicine. 2017:14(8):e1002369.

No funding information was provided for this study. Article processing fees were supported by the Canadian Institute of Health Research.

Bibliography

NICE. Low back pain and sciatica in over 16s: assessment and management. NG59. London: National Institute for Health and Care Excellence; 2016.

NICE. Medicines optimisation in long-term pain. KTT21. London: National Institute for Health and Care Excellence; 2017.

NICE. Neuropathic pain in adults: pharmacological management in non-specialist settings. CG173. London: National Institute for Health and Care Excellence; 2013 (updated 2017).

Why was this study needed?

Lower back pain is a common problem experienced by up to eight out of 10 people in the UK at some point in their lives. It can be very debilitating and affect the ability to carry out daily activities including work. Lower back pain is termed long-term when it has lasted for over three months. Often no clear cause can be found, particularly when there is no sciatica (leg pain suggesting direct pressure on a nerve) and finding a suitable treatment can be difficult.

For long-term low back pain, simple painkillers can be ineffective, and there is a move against prescribing stronger opioid-based pain-relief. Gabapentinoids are a group of antiepileptic drugs for the treatment of nerve pain that have been suggested as options for chronic lower back pain, though the evidence for this use is uncertain.

NHS Digital figures show NHS primary care prescriptions of pregabalin have increased more than ten-fold, from less than half a million in 2006 to just over 5.5 million in 2016. Gabapentin prescriptions have also risen from just over one million to 6.5 million over the same period. The commonest indication for this is neuropathic pain - in line with NICE guidance in 2013 (updated in 2017) which suggests a gabapentinoid as first-line treatment.

It is important to know whether they are effective for long-term lower back pain and whether there are any associated harms.

What did this study do?

This systematic review included eight randomised controlled trials assessing the effects of gabapentinoids in adults with chronic lower back pain.

Three trials compared gabapentin with placebo, three compared pregabalin with other drugs, and two looked at using pregabalin alongside other drugs.

Most studies were small and based in a single centre. None came from the UK. Chronic lower back pain had lasted for between one and 18 years, and treatment duration ranged from three to 14 weeks. Pain relief was measured on numerous scales. Evidence was judged to be low to very low quality for most outcomes.

Though trials of chronic lower back pain with or without leg pain were reportedly eligible, the researchers excluded trials in people with predominant leg pain or nerve compression. Only three trials questioned nerve pain specifically.

What did it find?

  • Gabapentin provided a non-significant improvement in pain compared to placebo. The standardised mean difference (SMD) was 0.22 units (95% confidence interval [CI] -0.5 to +0.07) on a patient-reported scale of 0 to 10, where lower numbers indicate less pain (three studies, 185 participants).
  • Pregabalin was less effective at reducing pain than the other medications. The SMD was 0.42, which is a moderate effect in favour of the other drugs (95% CI 0.20 to 0.64). This was from a meta-analysis of three studies (332 participants), one of which compared pregabalin with an antidepressant class drug (amitriptyline), one a type of anti-inflammatory (celecoxib) and one paracetamol combined with an opioid (Tramacet).
  • There was no benefit when pregabalin was given alongside the opioids tapentadol (SMD -0.04, 95% CI -0.26 to +0.18; one study, 306 participants) or buprenorphrine (SMD -0.42, 95% CI -1.02 to +0.17; one study, 44 participants). There was a small benefit when pregabalin was combined with celecoxib compared with celecoxib alone (SMD -0.81, 95% -1.29 to -0.33; one study, 72 participants).
  • Adverse events were more common with gabapentin and included dizziness (relative risk [RR] 1.99, 95% CI 1.17 to 3.37), fatigue (RR 1.85, 95% CI 1.12 to 3.05), difficulty thinking (RR 3.34, 95% CI 1.54 to 7.25), and visual disturbances (RR 5.72, 95% CI 1.94 to 16.91). People taking pregabalin were more likely to experience dizziness than those taking other active pain relief (RR 2.70, 95% CI 1.25 to 2.70).

What does current guidance say on this issue?

NICE guidelines on low back pain and sciatica in over-16s state that anticonvulsants should not be offered for managing low back pain. Self-management and exercise programmes are core components of care. Non-steroidal anti-inflammatories (NSAIDs) are the recommended drug treatment, with weak opioids (with or without paracetamol) considered only if NSAIDs are contraindicated, not tolerated or ineffective.

However, for management of sciatica NICE refer to their Neuropathic pain guidelines, which do recommend gabapentin or pregabalin as initial treatment options for neuropathic pain.

NICE Key Therapeutic Topic guidance (2017) notes that “The use of both gabapentin and pregabalin can lead to dependence and these medicines may be misused or diverted.”

What are the implications?

There are few effective drug treatments available for people with non-specific chronic lower back pain. There is no evidence at present to suggest that gabapentinoids are effective. Furthermore, the associated adverse events do not seem to justify prescribing them in this group.

This systematic review, in general, supports current NICE guidance on this topic. The grey area, however, is people with associated sciatica. The studies included in this review were not able to differentiate whether they may benefit.

GPs and Clinical Commissioning Groups may want to consider reviewing local usage of gabapentinoids in people with chronic lower back pain.

Citation and Funding

Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: a systematic review and meta-analysis of randomized controlled trials. PLoS Medicine. 2017:14(8):e1002369.

No funding information was provided for this study. Article processing fees were supported by the Canadian Institute of Health Research.

Bibliography

NICE. Low back pain and sciatica in over 16s: assessment and management. NG59. London: National Institute for Health and Care Excellence; 2016.

NICE. Medicines optimisation in long-term pain. KTT21. London: National Institute for Health and Care Excellence; 2017.

NICE. Neuropathic pain in adults: pharmacological management in non-specialist settings. CG173. London: National Institute for Health and Care Excellence; 2013 (updated 2017).

Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials

Published on 16 August 2017

Shanthanna, H.,Gilron, I.,Rajarathinam, M.,AlAmri, R.,Kamath, S.,Thabane, L.,Devereaux, P. J.,Bhandari, M.

PLoS Med Volume 14 , 2017

BACKGROUND AND OBJECTIVE: Chronic Low Back Pain (CLBP) is very common, with a lifetime prevalence between 51% and 80%. In majority, it is nonspecific in nature and multifactorial in etiology. Pregabalin (PG) and Gabapentin (GB) are gabapentinoids that have demonstrated benefit in neuropathic pain conditions. Despite no clear rationale, they are increasingly used for nonspecific CLBP. They necessitate prolonged use and are associated with adverse effects and increased cost. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse. We aimed to assess the effectiveness and safety of gabapentinoids in adult CLBP patients. METHODS: Electronic databases of MEDLINE, EMBASE, and Cochrane were searched from their inception until December 20th, 2016. We included randomized control trials reporting the use of gabapentinoids for the treatment of CLBP of >3 months duration, in adult patients. Study selection and data extraction was performed independently by paired reviewers. Outcomes were guided by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials guidelines, with pain relief and safety as the primary outcomes. Meta-analyses were performed for outcomes reported in 3 or more studies. Outcomes were reported as mean differences (MDs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs), and I2 in percentage representing the percentage variability in effect estimates that could be explained by heterogeneity. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of evidence. RESULTS: Out of 1,385 citations, eight studies were included. Based on the interventions and comparators, studies were analyzed in 3 different groups. GB compared with placebo (3 studies, n = 185) showed minimal improvement of pain (MD = 0.22 units, 95% CI [-0.5 to 0.07] I2 = 0%; GRADE: very low). Three studies compared PG with other types of analgesic medication (n = 332) and showed greater improvement in the other analgesic group (MD = 0.42 units, 95% CI [0.20 to 0.64] I2 = 0; GRADE: very low). Studies using PG as an adjuvant (n = 423) were not pooled due to heterogeneity, but the largest of them showed no benefit of adding PG to tapentadol. There were no deaths or hospitalizations reported. Compared with placebo, the following adverse events were more commonly reported with GB: dizziness-(RR = 1.99, 95% CI [1.17 to 3.37], I2 = 49); fatigue (RR = 1.85, 95% CI [1.12 to 3.05], I2 = 0); difficulties with mentation (RR = 3.34, 95% CI [1.54 to 7.25], I2 = 0); and visual disturbances (RR = 5.72, 95% CI [1.94 to 16.91], I2 = 0). The number needed to harm with 95% CI for dizziness, fatigue, difficulties with mentation, and visual disturbances were 7 (4 to 30), 8 (4 to 44), 6 (4 to 15), and 6 (4 to 13) respectively. The GRADE evidence quality was noted to be very low for dizziness and fatigue, low for difficulties with mentation, and moderate for visual disturbances. Functional and emotional improvements were reported by few studies and showed no significant improvements. CONCLUSIONS AND RELEVANCE: Existing evidence on the use of gabapentinoids in CLBP is limited and demonstrates significant risk of adverse effects without any demonstrated benefit. Given the lack of efficacy, risks, and costs associated, the use of gabapentinoids for CLBP merits caution. There is need for large high-quality trials to more definitively inform this issue. TRIAL REGISTRATION: PROSPERO CRD42016034040.

Expert commentary

The challenges of long-term low back pain cannot be overstated. Long-term low back pain costs are now estimated regarding a country's GDP, so how much resource does it consume. As some back pain has neuropathic features, it makes sense to explore the gabapentinoid family of analgesics.

This meta-analysis of eight published trials in unselected patients confirms that gabapentinoids offer little benefit, either alone or in combination with other analgesics. What they do provide is a high rate of adverse effects. Their use in unselected long-term low back pain is currently not supported. 

Frances MK Williams, Professor of Genomic Epidemiology & Honorary Consultant Rheumatologist, King’s College London

Expert commentary

Long-term low back pain is a common reason for consulting in primary care. In recent years there has been increasing awareness of the downsides of long-term opiate therapy, and there have been efforts to limit opiate prescribing, including “de-prescribing”. Conversely, the use of gabapentin and pregabalin appears to be increasing.

In this systematic review and meta-analysis of gabapentinoids for long-term low back pain, the quality of evidence identified was very low. No benefit of gabapentinoids was shown for this indication, but side effects were common. This information may help doctors talk with their patients about not prescribing, or de-prescribing, gabapentinoids.

The question of what we should prescribe instead remains.

Dr Sarah Mackie, Associate Clinical Professor & Honorary Consultant Rheumatologist, University of Leeds