Benzodiazepines and Opioids: Only Trained Pain Practitioners Should Prescribe
As one component of the effort to limit accidental opioid overdoses, the US Food and Drug Administration (FDA) announced in August 2016 that it was requiring class-wide changes to drug labeling, including patient information, to emphasize the serious risks associated with the concomitant use of benzodiazepines with opioids.1
FDA Commissioner Robert Califf, MD, said, “It is nothing short of a public health crisis when you see a substantial increase of avoidable overdose and death related to 2 widely used drug classes being taken together.”
I salute this effort because it is the combination of opioids with central nervous system (CNS)–depressant drugs, including alcohol, benzodiazepines, and non-benzodiazepine hypnotics, that causes extreme sleepiness, respiratory depression, and increases risk of overdose death.2
While the vast majority of opioid-related overdoses do not involve chronic pain patients, pain patients in active treatment who take a combination of opioids and CNS depressants are at higher-than-normal risk of falls, motor vehicle accidents (MVAs), and accidental overdose.3
A study conducted in 2011 found that the benzodiazepines diazepam, flurazepam, flunitrazepam, nitrazepam, and the short-half-life non-benzodiazepine hypnotic zopiclone, significantly impaired driving, at least during the first 2 to 4 weeks of treatment.4
Unfortunately, it is rare that a severe chronic pain patient will not need a combination of opioids and a CNS depressant.5,6 A population study conducted in Norway found that 60% of chronic pain patients on long-term opioids were also prescribed “a benzodiazepine or benzodiazepine-related hypnotic in amounts indicating regular use, with 15% dispensed a high amount of both classes.”7 In addition, 62% of long-term opioid patients in the study were dispensed 1 or more non-opioid analgesics—47% received an anti-depressant and 33% were dispensed an antiepileptic drug.7
The FDA warning does not include just benzodiazepines but also includes “other depressants.”1 Practically all our armamentarium for severe chronic pain are depressant drugs:
- antiseizures (gabapentin, topiramate, etc)
- muscle relaxants (tizanidine, carisoprodol, etc)
- antidepressants (duloxetine, amitriptyline, etc)
Simply put, care of severe pain necessitates CNS-depressant drugs. The extraordinary value of benzodiazepines for chronic pain has long been known, and the increasing concomitant use of opioids and benzodiazepines is testimony to the effectiveness of this combination.6
The actual “black box” warning (Table 1) makes it essential that all pain practitioners know that benzodiazepines and other depressants are not banned or prohibited. The warning is the proverbial yellow light—“proceed with caution.” As noted in a press release by the FDA: “Benzodiazepines are drugs typically prescribed for the treatment of neurological and/or psychological conditions, including anxiety, insomnia, and seizure disorders. Both classes of drugs depress the central nervous system; however, each has unique pharmacology, safety risks, and labeling information related to its use. Therefore, the FDA is requiring opioid analgesics, prescription opioid cough products, and benzodiazepines to have slightly different labeling. Additionally, due to the unique medical needs and benefit/risk considerations for patients undergoing medication-assisted treatment (MAT) for opioid addiction and dependence, the FDA is continuing to examine available evidence regarding the use of benzodiazepines and opioids used as part of MAT.”
Where to Go From Here
So where do we go from here? And what is our liability if a patient on combination therapy has a fall, MVA, or overdose?
A critical first step is to inform every pain patient about the new warning. They should know that this warning is already causing some insurance carriers to screen for patients taking combinations of medications and to deny coverage. Second, every patient has to be aware of the risks of falls, MVAs, and diversion of these drugs by relatives or visitors to their home. Third, to prevent falls and MVAs, it may be safer to limit or reduce depressant dosages and raise opioid dosages.
Pure opioid overdoses without a sedative are rare in pain patients.2 Patients who concomitantly take an opioid and benzodiazepine or other depressant must be regularly monitored for evidence of sedation and impairment. For example, I recommend a monthly visit to begin with. A written special consent agreement stating the hazards of opioid and depressant use is a strong consideration. Each pain practitioner or group should set policies known to all regarding depressant dosages, number of take-home capsules/tablets, and withdrawal schedules.
Two clinical management points come to mind: when initiating a benzodiazepine or other depressant, start the dose “low and go slow” when increasing it; and regularly monitor the patient and record in the patient’s chart whether the patient is alert, has mental clarity, walks normally, and has normal blood pressure/pulse. In case the patient falls, has an MVA, or overdoses, you will have chart evidence that the patient was tolerant to the depressant and not impaired or sedated.
Be clearly advised that most chronic pain patients who have been in treatment for some time may not be on only 1 but 2 or 3 CNS-depressant drugs. In addition, they may be stable, tolerant, and functioning well. Patients are not willing and should not have to reduce their depressant dosages. The FDA warning does not require any mandatory reductions. A critical point to be made in this matter is that most patients become tolerant quite rapidly to the depressant effects of benzodiazepines and other depressant drugs used in pain management. Consequently, most chronic pain patients can take 2 or 3 depressants in the same day and exhibit no evidence of respiratory depression, suppression of the cardiovascular system, constriction of the pupil, or interference with mental and physical functions.
It needs to be clear to all concerned parties that we can’t relieve pain and suffering without benzodiazepines and other depressants.5,6 Opioids are a pharmacologic relative of endorphins, while benzodiazepines are a relative of g-amino butyric acid (GABA). Both endorphins and GABA are essential for endogenous, natural pain control. Benzodiazepines may enhance the GABA system so that the pain patient may get some sleep. Also, deficiencies in this system caused by severe pain may cause excess sympathetic discharge.
Those severe, chronic pain patients who have centralized their pain will produce a constant barrage of descending sympathetic pain signals, which produce hypertension, tachycardia, hyperhidrosis, hyperthermia, fatigue, and weakness. In some chronic pain patients, only a benzodiazepine or other depressant can control the pathologic consequences of centralized pain.