Reappraising the use of benzodiazepines in chronic pain patients

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KEYWORDS:

• Benzodiazepines
• benzodiazepine dependence
• chronic pain
• benzodiazepine addiction
• anxiety
• insomnia

Benzodiazepines are not indicated for pain control, but they are frequently taken by pain patients. Indeed, benzodiazepines are among the most widely prescribed drugs on earth despite the fact that they are known to cause tolerance, dependence, and be associated with side effects [1,2]. Their unfortunate popularity among pain patients is troubling as many pain patients take concomitant opioids and the benzodiazepine-opioid combination can lead to potentially life-threatening respiratory depression. The Centers for Disease Control and Prevention (CDC) in their 12-point guidelines to primary care physicians who prescribe opioids specifically advised against the concurrent use of a benzodiazepine with an opioid [3]. About 30% of opioid-associated overdose deaths involve the use of a benzodiazepine. [4] A cohort study found that the risk of death was increased 10-fold for opioid patients who took a benzodiazepine at the same time (7.0 per 10,000 person-years, 95% confidence interval, 6.3–7.8 versus 0.7 per 10,000 person years, 95% confidence interval, 0.6-0-.9) [5].

Benzodiazepines, which first came to market to replace carbamate drugs and the useful but extremely habit-forming drug class of barbiturates, act as positive allosteric modulators of the gamma-aminobutyric acid (GABA) receptor A, producing sedative, anxiolytic, hypnotic, anticonvulsant, and muscle-relaxing effects [6]. GABA is the single most common neurotransmitter in the body and it has an inhibitory effect on excitable neurons, which can result in a calming or dampening effect on cerebral activity [6].

Benzodiazepines are indicated for short-term use to treat acute anxiety and acute insomnia, both of which can occur with acute and chronic painful conditions [7–11]. In addition, benzodiazepines are widely prescribed off-label for a variety of mental health conditions, including depression, posttraumatic stress disorder, schizophrenia, obsessive-compulsive disorder, and others [12–15]. In the case of posttraumatic stress disorder, the use of benzodiazepines is not only contraindicated but it may exacerbate symptoms [12,16].

There is a paucity of evidence in the literature as to why pain patients are prescribed benzodiazepines. One may surmise that many people struggling with pain, particularly chronic pain syndromes, may report distressing symptoms of stress, anxiety, fearfulness, and disordered sleep patterns, any of which might be considered a reasonable indication for a benzodiazepine. Nevertheless, benzodiazepines are intended for short-term use only, typically defined as under four weeks, although they are increasingly prescribed for long-term and even open-ended, indefinite use [17]. Package inserts often do not urge caution about extended use other than their effectiveness over longer periods of time has not been systematically studied in clinical trials.

In a cohort study of 847 consecutive patients admitted to a three-week interdisciplinary pain rehabilitation program conducted in 2013 to 2014, patients’ medical histories, drug use, and other demographic and psychological factors were studied. Female sex was also associated with benzodiazepine use in this study. About a third of these patients (29.3%) were taking benzodiazepines and of that subset, most (62%) were taking opioids along with benzodiazepines. The patients taking benzodiazepines (with or without opioids) reported greater pain severity, more symptoms of depression, and higher rates of catastrophizing than the pain patients not taking benzodiazepines [18].

Benzodiazepine-associated side effects span a wide range of symptoms, some of which mimic the underlying diseases or disorders the benzodiazepines are supposed to treat. For instance, benzodiazepines may cause anxiety, restlessness, agitation, fearfulness, sedation, fatigue, somnolence, and confusion [1]. This potential symptom overlap may lead to misdiagnoses, for instance, a patient suffering anxiety along with chronic pain may experience a sudden exacerbation in her anxiety – but is that the result of too much benzodiazepine or too little? It may well be the former, and if she is instead prescribed a higher dose or another benzodiazepine, it may well exacerbate her condition. It must be noted that tolerance to benzodiazepines can develop rapidly [19] and there may be cases where the underlying anxiety-related condition is breaking through. But in many cases, symptoms of anxiety may be the paradoxical result of chronic benzodiazepine use [2].

The short-term use of benzodiazepines would be considered appropriate, for example, to help a trauma patient navigate a difficult week through hospitalization and treatment. While this patient may be in pain, the benzodiazepine therapy would be for the acute management of anxiety and fear associated with the accident and its abrupt terrible consequences. The short-term use of a benzodiazepine in such a situation is rarely problematic when the benzodiazepine is discontinued after a few days or weeks. Benzodiazepines were not ever intended for long-term use, although they are often used that way. In fact, the main indications for benzodiazepine therapy that might affect pain patients are anxiety, insomnia, and muscle spasms, which are typically chronic rather than acute conditions. In cases of acute pain, benzodiazepine use is discontinued along with the analgesics when the pain resolves. But what then is the role of benzodiazepines for long-term use in chronic pain? Chronic pain is by definition chronic, so benzodiazepines are not appropriate to use to treat this condition. Not only would this be off-label, it appears counterproductive [1,20]. But there are important unanswered questions about prescribing patterns. For example, which comes first, the benzodiazepine or the chronic pain? Do symptoms of anxiety or insomnia develop slowly over time with chronic pain and then result in benzodiazepine use? Are there chronic pain patients who experience paroxysmal acute episodes of anxiety or insomnia and, if so, why?

A study of 114 chronic pain patients treated at a three-week interdisciplinary pain program in 2013 to 2014 found 38% were taking benzodiazepines (and of that group, 46% had been taking benzodiazepines for at least two years) although benzodiazepines provided little to no therapeutic benefit and chronic pain patients taking benzodiazepines had the same levels of pain and insomnia as those who did not take benzodiazepines. [21] A study of 1,220 chronic noncancer pain patients on chronic opioid analgesic treatment found that about a third had used benzodiazepines in the past month (33%) and benzodiazepine use was associated with greater pain severity, more interference by pain with daily life, lower feelings of self-efficacy in terms of pain control, substance use disorder, mental health comorbidities, and the likelihood of being on antipsychotic or antidepressant drugs [22].

Chronic pain is a complex condition in that it involves physical as well as psychological and social components. The comorbid connection between certain mental health disorders and chronic pain have not yet been fully elucidated. For example, neuroinflammation appears to play a role in both depression and chronic pain [23]. Chronic pain has also been associated with anxiety, negative thought patterns, and problems sleeping (which may be due to mental or physical problems) [24], any of which may lead a clinician to consider the use of a benzodiazepine. However, benzodiazepines are habit-forming drugs that produce side effects and may interfere with the patient’s ability to participate in health-promoting, pain-fighting activities such as daily exercise, psychological therapy, social activities, and so on. They may also worsen anxiety and they can produce a myriad of other symptoms that the patient may wrongly attribute to the underlying painful condition, further fueling the vicious cycle of pain and hopelessness/helplessness [1].

Benzodiazepines do not relieve pain, although they can offer acute relief for anxiety, insomnia, or muscle spasms, provided they are used for a short period of time. However, they are not first-line treatments for anxiety, insomnia, and are not indicated at all for chronic pain or mental health conditions such as depression, posttraumatic stress, or personality disorders [16,25]. Greater prescriber education is needed and an awareness that long-term use of benzodiazepines may create more (and more onerous) problems than they solve[1]. Benzodiazepine therapy should only ever be initiated when the patient is aware of the risks as well as benefits of these drugs, understands what physiologic dependence is, and has a clear understanding that the drug will be discontinued after a short time. Benzodiazepine therapy should only ever be started when there is an exit plan in place.

Declaration of interest

The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.