The gabapentinoids, gabapentin and pregabalin, are derivatives of the neurotransmitter gamma-aminobutyric acid (GABA). Both are licensed for the treatment of seizure disorders and neuropathic pain conditions in the UK and USA, and, additionally, in the USA for restless leg syndrome (RLS).1, 2 Pregabalin is also licensed for generalised anxiety disorder (GAD) in the UK although it is not recommended as a first-line option and reserved for use if SSRIs or SNRIs are not tolerated.3 Pregabalin and gabapentin are also often used off-licence ('off-label') for a number of conditions for which there is a lack of evidence of efficacy4 including migraine, low back pain, sciatica, alcohol use disorders, insomnia and bipolar disorder, and anxiety disorders (off-licence for gabapentin). Off-label use may mean that patients are exposed to harms without clear benefits (Table 4.1 ).4, 7 Up to 80% of gabapentin use is off-label in the USA.8 Gabapentin, in particular, has been described as a 'catch-all' medication that has come to be used in a wide variety of disorders.9
Table 4.1 Licensed Indications and Unlicensed Uses for Gabapentinoids in the USA and Uk
| Drug | Licensed indications | Unlicensed uses | |
|---|---|---|---|
| Pregabalin | USA10 |
|
|
| UK11, 12 |
|
| |
| Gabapentin | USA13 |
|
|
| UK11, 12 |
|
|
The prescribing of gabapentinoids in England has increased dramatically in recent years, rising from less than 1 million prescriptions in 2008 to 16 million in 2022 with roughly equal representation of the two drugs.15, 16 In 2017-2018 1.46 million people in England received at least one prescription for a gabapentinoid.15 In the USA the use of gabapentinoids more than trebled from 2002 to 2015, from 1.2% of adults to 3.9% of adults, with more than 80% of these prescriptions for gabapentin.17 In 2018 gabapentin became the sixth most commonly prescribed medication in the USA.18 It has been suggested that this rise in prescribing has been due to a desire to avoid opioid analgesics.7 Approximately one-tenth of the prescriptions for pregabalin are for anxiety.19
Off-label prescribing of gabapentinoids is widespread. In the UK around half (51.4%) of patients prescribed pregabalin and just over a third (36.9%) of patients prescribed gabapentin had a diagnosis for a licensed indication.11 As with the case of OxyContin, pharmaceutical companies marketing gabapentinoids have paid large fines for misrepresentation of their safety and misuse potential, as well as for promoting prescribing for off-label indications, and so inflating demand.20 In the USA, gabapentinoids are now prescribed during one in four post-surgical admissions, often in combination with opioids or other analgesics, presumably with an aim to reduce opioid consumption, despite a lack of evidence for peri-operative pain or for opioid-sparing effects.21 Longer-term off-label prescribing of gabapentinoids has mostly been seen in the treatment of chronic low back pain. This use leads to wide availability among a population already vulnerable to misuse, and often in conjunctive with multiple co-prescribed sedative or analgesic medications, increasing the risk of harms.22
In the UK gabapentinoids were re-classified as Class C Controlled Drugs under the Misuse of Drugs Act from 2019 and Schedule 3 controlled drugs under the Misuse of Drugs Regulation. This was in recognition of escalating misuse, diversion and addiction, as well as growing numbers of deaths associated with their use.23, 24 This scheduling places them in the same category as higher-risk benzodiazepines (e.g. midazolam and temazepam).23, 24 Under the Misuse of Drugs Act unlawful possession, production or supply of these drugs is subject to potential punishment and fines. In the USA, the FDA has issued warnings about the use of gabapentinoids in people with respiratory depression especially in those patients also using opioid medication, those with lung conditions like chronic obstructive pulmonary disease (COPD), and the elderly.2 Pregabalin has been a Schedule V drug (indicating the lowest potential for abuse compared to other scheduled drugs) under the Controlled Substances Act since 2005,25 and some states have classified gabapentin under the same schedule.26
Public Health England conducted a review of dependence-forming medicine in England in 2019 and reflected:
Recurring patterns are evident in the history of medicines that may cause dependence or withdrawal. New medicines are seen as an important part of the solution to a condition, resulting in widespread use. Their dependence or withdrawal potential are either unknown at this point, due to a lack of research, or perhaps downplayed. As evidence of harm from dependence or withdrawal emerges, efforts are made to curtail prescribing. The repetition of this pattern is striking.
Some commentators have suggested that gabapentinoid use is a clear example of this pattern.27
Gabapentinoids are structurally similar to GABA, rapidly cross the blood-brain barrier and although their mechanism of action is poorly understood, seem to exert their effects through inhibition of alpha-2-delta sub-unit-containing voltage-dependent calcium channels.28 This inhibition prevents synaptic release of glutamate and norepinephrine, and is thought to reduce neuronal excitation.28 Although gabapentinoids are not thought to directly bind to GABA receptors they do dose-dependently increase levels of GABA, and thus have weak GABA-mimetic effects.28, 29 They therefore have some overlap with the pharmacological effects of benzodiazepines, which also increase GABA activity.5 This pharmacological similarity is reflected in their shared short-term anxiolytic, anticonvulsant and analgesic properties, as well as their ability to cause dissociation, relaxation, a sense of calm and, in some, euphoria.21, 30
There are some pharmacological differences between the gabapentinoids. Pregabalin has higher potency, greater bioavailability (90%, or greater, compared with 33-60% for gabapentin) and quicker absorption than gabapentin (reaching maximum plasma concentrations within 1 hour compared with 3-4 hours for gabapentin).28, 30 It has been observed that pregabalin is more prone to abuse than gabapentin, which may be because of its ability to induce a more rapid euphoria due to its pharmacodynamic and pharmacokinetic characteristics.28
The evidence for the efficacy of pregabalin in anxiety is somewhat limited. Anxiety can be a long-term condition requiring long-term treatment that necessitates long-term trial data. However, the manufacturer's guide to pregabalin states that it has been studied in six controlled trials of 4-6 weeks duration and in one study of 8 weeks.31 If the results of these trials are presented as response (greater than a 50% improvement in Hamilton Anxiety (HAM-A) scores), pregabalin is superior to placebo (52% response for pregabalin, 38% for placebo).31 However, examination of the raw HAM-A data before dichotomisation can be informative. A recent meta-analysis of these short-term studies, in addition to unpublished studies by drug manufacturers, found pregabalin reduced HAM-A scores by 2.8 points compared with placebo at 4-10 weeks follow-up.32 On the 56-point HAM-A, it is unclear whether this effect is clinically meaningful. More importantly, the short duration of treatment (average 7.3 weeks)32 in these studies may not be informative about the treatment of anxiety, an often chronic condition commonly needing to be treated for months or years.
In a similar manner to benzodiazepines, tolerance to the effects of pregabalin develops over time.33 It is therefore likely that, as for benzodiazepines,34 its anxiolytic properties will lessen over time, diminishing or eliminating these short-term effects. Unfortunately, no useful study has been conducted that lasts longer than 10 weeks to evaluate this possibility.
These studies also did not examine the difficulty of withdrawing from these drugs. There is one discontinuation study evaluating relapse-prevention properties in GAD, which involved abrupt stoppage of pregabalin from a dose of 300mg after 8 weeks of treatment.35 The authors neglected measurement of the recognised withdrawal effects that can mimic the symptoms of relapse and can inflate the detection of relapse in the discontinuation arm, rendering this study difficult to interpret.35
According to NHS guidance, no more than one-quarter of patients with certain long-term pain conditions (including painful diabetic neuropathy, pain following stroke and post-herpetic neuralgia) receive any benefit from gabapentinoids.36, 38 A 50% reduction in pain is experienced by even fewer.36, 38
NHS guidance encourages review of gabapentinoids for neuropathic pain and advises that they should be gradually discontinued if ineffective.39 This guidance suggests that even people who think they are obtaining benefit from the use of pregabalin or gabapentin should undertake a trial dose reduction periodically, to ensure they are benefiting and to see if they can derive the same benefit on a lower dose.39 This guidance also highlights that gabapentinoids are licenced for neuropathic pain and are very unlikely to be of benefit when prescribed for non-neuropathic pain.40
Moderate-quality evidence supports the use of gabapentinoids to improve pain in post-herpetic neuralgia or diabetic peripheral neuropathy in short-term studies (up to 16 weeks).36, 37 At time points up to 16 weeks almost 40% of people taking pregabalin and 30% of people taking gabapentin had at least 50% pain relief.36, 37 There are no long-term studies of the effect of these drugs, but tolerance might be anticipated, as with opioids.33
Only 10% of patients with moderate to severe fibromyalgia experienced a 50% reduction in pain over several months of treatment according to high-quality evidence from a Cochrane review.41 Evidence for gabapentin is inconclusive because of the small number of low-quality trials.42 These drugs are probably not effective for pain relief in other conditions and their use is not advised.7 Systematic reviews have found no benefit of gabapentinoids over placebo in low back pain, sciatica, spinal stenosis or episodic migraine in adults.7 Currently, there is insufficient evidence to support the use of pregabalin in acute pain, HIV neuropathy, neuropathic cancer pain and other forms of neuropathic pain.7
In chronic primary pain (pain which lasts for more than 3 months and for which no underlying condition is identified as the cause), UK NICE guidelines advise against using gabapentinoids, unless as part of a research trial.43 This guideline recommends that patients who are already on gabapentinoids for primacy pain should be informed of the lack of evidence for these medications and the risks of continuing. Those with little benefit or evidence of significant harm should be encouraged to reduce and stop.43 For those who report benefit and few harms continuing safely is also presented as an option.43
According to the UK manufacturer for pregabalin there are 47 adverse effects that are either common or very common (though the baseline rate for placebo was not taken into account) (Table 4.2 ).31 Nearly two-thirds of patients taking these drugs for neuropathic pain experience an adverse event.7 Very common adverse effects as reported by the manufacturer or Cochrane review include dizziness (19%), somnolence (14%) and headache (more than 10% of patients).31, 36 Other common psychiatric adverse effects include euphoric mood, confusion, irritability, decreased libido, disorientation and insomnia, all occurring in 1-10% of patients.31 The manufacturer also reports on the patient label that increased risk of new-onset suicidal behaviour and death by suicide has been demonstrated in self-controlled studies (where periods on a drug are compared to periods off the drug in the same individual).31 NHS guidance also highlights problems with sedation, weight gain, mood changes, hallucinations, muscle and joint pain, sexual dysfunction and impaired immune response.39 Adverse events from gabapentinoids frequently result in discontinuation of the drug. For example, almost 30% of patients with fibromyalgia withdrew from studies because of adverse effects (compared with 11% for placebo).41
Table 4.2 Very Common (Experienced by More Than 10% of Participants) and Common (1-10% of Participants) Adverse Effects of Pregabalin
| Psychiatric | Cognitive | Neurological |
Euphoric mood Irritability Insomnia Panic attacks Restlessness Agitation Depressed mood Aggression Mood swings Depersonalisation Abnormal dreams Apathy | Disorientation Memory impairment Impaired attention Confusion | Dizziness Somnolence Headache Ataxia Abnormal co-ordination Tremor Dysarthria Paraesthesia Sedation Balance problems |
| Miscellaneous | Musculoskeletal | Gastrointestinal |
Blurred vision Diplopia Vertigo Erectile dysfunction Nasopharyngitis Weight gain Increased appetite Decreased libido/anorgasmia | Muscle cramp Arthralgia Back pain Pain in limb Cervical spasm | Vomiting Nausea Dry mouth Constipation Diarrhoea Flatulence Abdominal distension |
There are specific risks when gabapentinoids are given with opioids. Co-prescription should usually be avoided because of an increased risk of respiratory depression, accidental overdose and death.39 The Medicines and Healthcare Products Regulatory Agency (MHRA) warning states that in cases of existing co-prescription the patient should be evaluated for these risks and either the gabapentinoid or the opioid reduced appropriately.44
Longitudinal studies have found that gabapentin is associated with neurocognitive and functional decline in older adults, including a more than doubling in risk of falls.46 Gabapentinoids have also been associated with sexual dysfunction in people with epilepsy.47 In young people, gabapentinoids have also been associated with increased risk of suicide, unintentional overdose, road traffic accidents, and head and body injuries - with stronger associations for pregabalin than for gabapentin.30
In 2022, the UK's MHRA issued an updated warning on pregabalin use during pregnancy, recommending effective contraception throughout treatment and to avoid pregabalin use during pregnancy unless clearly necessary.48, 49 These recommendations were updated in the context of a Nordic study of over 2,700 pregnancies, demonstrating higher crude rates of major congenital malformations in pregnancies exposed to pregabalin compared to pregnancies unexposed to pregabalin or other antiepileptic drugs (5.9% vs 4.1%, respectively), and a modestly increased risk of major congenital malformations in neonates exposed to first-trimester pregabalin compared to those exposed to lamotrigine or duloxetine.50
According to the UK Office of National Statistics (ONS) records of coroners' reports deaths associated with pregabalin have increased more than 10-fold in the 7 years from 2014 to 2021 (perhaps partially explained by more testing).51 In 2021 there were more deaths in England and Wales involving pregabalin (409) than diazepam (290) or fentanyl (58).51 It should be noted that, like diazepam, pregabalin's lethality is probably attributable to combined use with opioids, possibly because of the ability of pregabalin to reverse tolerance to opioid depression of respiration:52 indeed pregabalin is rarely the sole drug present in poisonings.53
When mortality is corrected to prescriptions issued per year, mortality for pregabalin has also risen approximately 10-fold in the last 7 years.54 Its mortality per prescription is less than that for diazepam and fentanyl, although rising more steeply.54 Gabapentinoids (along with z-drugs) have been associated with a 3-fold increase in overdose deaths in the USA from 2000 to 2018, leading to a warning to prescribers that replacing benzodiazepines and opioids with these medications did not necessarily lower the risk to the patient.55
Anxiety
Most analyses find little difference between psychotherapy and pharmacotherapy for anxiety disorders.56, 57 There is a non-significant benefit for psychotherapy over pharmacotherapy for anxiety disorders in general (though strongly significant (g = 0.64) for OCD).57 An umbrella review of meta-analyses found that psychotherapies achieved SMDs (standard mean differences) of between 0.28 and 0.44, while pharmacotherapies achieved SMDs of 0.33 and 0.45.58 Most guidelines recommend psychotherapeutic options, including CBT and other modalities for the treatment of generalised anxiety disorders.3
For chronic primary pain the NICE guidelines recommend supervised group exercise, remaining physically active, acceptance and commitment and cognitive behavioural therapies, specific acupuncture interventions and antidepressant medication.43 (However, in a recent overview of systematic reviews, antidepressants were found to be ineffective, effective to a clinically dubious degree or analyses were found to be inconclusive,59 leading to a re-consideration of the guidance.)60 The provision of individualised therapy, support and social activities encouraging de-medicalisation, independence and personal development in one community pain clinic working with a charity led to a 50% reduction in prescribing, as well as improved pain and function.61 It also reduced use of specialist outpatient services by 50%.61 In the US, the department of Health and Human Services in its Best Practice guide for pain management, outlines four approaches to pain aside from medication including restorative therapies, interventional procedures, behavioural health approaches and complementary and integrative health.62