Using Buprenorphine for Chronic Pain Management

Is buprenorphine the future of chronic pain treatment?

woman-in-pain
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At face value, the opioid crisis and chronic pain are directly opposed. Although the CDC points out that “evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited, with insufficient evidence to determine long-term benefits versus no opioid therapy,” the fact remains that opioids are the principal intervention for the treatment of chronic pain.

Although primary care providers can prescribe opioids for chronic pain, they are reluctant to do so for fear of patient overdose or dependence. Most primary care physicians find the prospect of giving patients opioids for a long period of time too stressful and quickly refer these patients to pain specialists.

Despite reluctance to treat it, chronic pain is becoming increasingly frequent. In 2010, 31 percent of Americans experienced chronic pain, which is defined as pain lasting more than three to six months. Because the vast majority of people with chronic pain present to primary care physicians, it would be a breakthrough if we had some safe and effective alternative to opioids—some medication that these physicians would feel comfortable prescribing. A medication called buprenorphine may someday help fit this bill.

What Is Buprenorphine?

Buprenorphine belongs to a class of drugs called opioid partial agonist-antagonists.

In addition to another drug which combines buprenorphine and naloxone (Suboxone), buprenorphine is used as opioid substitution therapy to treat opioid dependence (dependence on heroin or prescription narcotics). These drugs work by preventing withdrawal symptoms when a person who is dependent on opioids stops taking opioids.

Buprenorphine is a semisynthetic opioid derivative of the opium alkaloid thebaine, which is found in the opium poppy (Papaver somniferum). It actually took decades for researchers to synthesize the drug, and there were many failed attempts before an English pharmaceutical company finally made it in 1966. By 1978, an intravenous formulation of buprenorphine was introduced, followed by a sublingual (applied under the tongue) iteration in 1982. In 1985, buprenorphine was introduced in the United States as an opioid analgesic.

How It Works

Buprenorphine has very specific mechanisms of action that make it enviable not only for treating opioid dependence but possibly chronic pain, too.

First, buprenorphine has a high binding affinity for the μ-opioid receptor, which is responsible for pain relief. Moreover, buprenorphine has a slow rate of dissociation from the μ-opioid receptor, meaning that it stays attached longer to the receptor, and has prolonged effect.

Second, although buprenorphine likes the μ-opioid receptor quite a bit, it acts only as a partial μ-opioid receptor agonist, which means that while buprenorphine prevents opioid withdrawal, its actions are less potent than opioids.

Third, buprenorphine is a full κ-opioid receptor antagonist.

Activation of the κ-opioid receptor results in the euphoric and psychotic effects of opioids. In other words, buprenorphine won’t make you “high.”

Administration

As mentioned earlier, naloxone is often combined with buprenorphine in the form of Suboxone. Naloxone is a short-acting, opioid receptor antagonist. When combined in low doses with buprenorphine,  naloxone can counteract dangerous opioid side effects—including respiratory depression, sedation, and hypotension—without diminishing analgesia, or pain relief. Furthermore, the addition of naloxone to buprenorphine serves as a deterrent to substance abuse.

According to the NIH:

"​Buprenorphine comes as a sublingual tablet. The combination of buprenorphine and naloxone comes as a sublingual tablet (Zubsolv) and as a sublingual film (Suboxone) to take under the tongue and as a buccal [cheek] film (Bunavail) to apply between the gum and cheek."

Buprenorphine also comes in a transdermal patch, intravenous formulation, and, most recently, a sublingual spray. In December 2017, it was announced that the FDA was reviewing the new sublingual spray for treatment of acute pain.

Side Effects

Although not nearly as dangerous as opioids, both buprenorphine and Suboxone can have negative side effects including the following:

  • Back pain
  • Blurred vision
  • Constipation
  • Difficulty with sleep
  • Mouth numbness
  • Headache
  • Stomach pain
  • Tongue pain

More serious side effects, such as difficulty breathing or swelling of the mouth or tongue, require immediate medical attention. Importantly, mixing buprenorphine with other drugs like benzodiazepines can be lethal.

Buprenorphine for Chronic Pain

In a systematic review published in December 2017, Aiyer and co-authors examined the efficacy of buprenorphine for the management of chronic pain. The researchers analyzed 25 randomized controlled trials involving five buprenorphine formulations:

  • Intravenous buprenorphine
  • Sublingual buprenorphine
  • Sublingual buprenorphine/naloxone (Suboxone)
  • Buccal buprenorphine
  • Transdermal buprenorphine

Overall, the researchers found that 14 of 25 studies suggested that buprenorphine in any formulation was effective for the treatment of chronic pain. More specifically, 10 of 15 studies showed that transdermal buprenorphine was effective, and two of three studies showed that buccal buprenorphine was effective. Only one of six studies indicated that either sublingual or intravenous buprenorphine was effective for the treatment of chronic pain. Importantly, no serious adverse effects were reported in any of the studies, which indicates that buprenorphine is safe.

In 2014, Cote and co-authors published a systematic review examining the efficacy of sublingual buprenorphine for the treatment of chronic pain. Although the majority of studies they analyzed were observational and low-quality, the researchers did find that sublingual buprenorphine was effective at treating chronic pain. Notably, Cote and co-authors compiled the following list of potential benefits of buprenorphine:

  • Increased efficacy in neuropathic pain due to its unique pharmacological profile.
  • Ease of use in the elderly and in renal impairment due to its minimal effect on half-life and metabolites.
  • Less immunosuppression compared with morphine and fentanyl based on very limited evidence from preclinical and clinical work.
  • Ceiling effect for respiratory depression when used without other central nervous system depressants, perhaps because the intrinsic activity to produce analgesia may be less than that of respiratory depression.
  • Less effect on hypogonadism, as demonstrated in maintenance therapy.
  • Less development of tolerance, possibly through kappa receptor antagonism or opioid-receptor-like (ORL-1) agonism.
  • Antihyperalgesic effect, perhaps due to kappa receptor antagonism or ORL-1 agonism.
  • Antidepressant effect in patients unresponsive to conventional therapy.

Interestingly, it’s hypothesized that because of its binding properties, buprenorphine may be able to help people who experience opioid-induced hyperalgesia.

In an article titled “A comprehensive review of opioid-induced hyperalgesia,” Lee and co-authors opioid-induced hyperlagesia as the following:

"Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients."

Of note, nociceptive pain is the sharp pain resulting from damage to a body part. It’s hypothesized that buprenorphine has antinociceptive properties. 

In a 2014 article published in Anesthesiology, Chen and co-authors write the following:

"Buprenorphine has been shown to reverse hyperalgesia induced by opioids through ‘buprenorphine-induced antinociception.’ Moreover, buprenorphine is a κ-receptor antagonist and can compete with the effect of spinal dynorphin, an endogenous κ-receptor agonist. Because spinal dynorphin is increased after opioid exposure and contributes to OIH, this competitive effect of buprenorphine on the κ-receptor binding site may decrease the effect of spinal dynorphin resulting in the decreased OIH."

Prescribing Buprenorphine

To a limited extent, in the United States, buprenorphine is already being used to treat chronic pain. Suboxone is prescribed off-label for the treatment of chronic pain. Furthermore, the transdermal buprenorphine patch is available for the treatment of severe chronic pain in the United States.

However, there is no consensus opinion with regard to the efficacy of using buprenorphine for this purpose. Currently, the few studies examining the effect of buprenorphine on chronic pain are too disparate in their approaches, and are thus too difficult to compare with one another.

Before the prescription of buprenorphine for the treatment of chronic pain becomes an evidence-based practice, various issues would need to be resolved. For example, current studies use a variety of pain rating scales when evaluating efficacy thus providing an inconsistent analysis. Pain rating scales in studies examining buprenorphine would need to be standardized. Furthermore, dosing strategies and route of administration would need to be examined for different presentations of chronic pain.

If the prescription of buprenorphine for chronic pain were ever to become evidence-based, primary care physicians would ostensibly be primed for this practice. In 2000, the U.S. Drug Addiction Treatment Act made it legal for primary care physicians to provide opioid substitution therapy using Schedule III, IV, and V drugs. In 2002, the FDA approved out-patient treatment with buprenorphine, characterizing it as a Schedule III drug.

All that a primary care physician needs to do to be able to prescribe buprenorphine in an out-patient setting is to complete eight hours of training. Nevertheless, few primary care providers have become eligible to prescribe buprenorphine.

Although many primary care physicians would likely bristle at the suggestion, it wouldn’t be that big of a stretch to think that primary care physicians could someday treat chronic pain in the outpatient setting using buprenorphine. In addition to primary care physicians having the ability to prescribe buprenorphine, the CDC also has guidelines in place for primary care physicians to treat chronic pain with opioids.

Essentially, the CDC guidelines recommend that primary care physicians prescribe opioids for chronic pain only when non-opioid treatments are not sufficient, and to prescribe opioids at the lowest dose possible. In this context, buprenorphine could essentially be considered an opioid alternative.

Sources:

Aiyer R, et al. Treatment of Chronic Pain With Various Buprenorphine Formulations: A Systematic Review of Clinical Studies. Anesthesia & Analgesia. 2017. [epub ahead of print]

Chen KY, Chen L, Mao J. Buprenorphine–Naloxone Therapy in Pain Management. Anesthesiology. 2014; 120(5):1262-74.

Cote J, Montgomery L. Sublingual Buprenorphine as an Analgesic in Chronic Pain: A Systematic Review. Pain Medicine. 2014;15:1171-1178.

Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. MMWR. 2016;65(1):1-49.

Lee M, et al. A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician. 2011; 14(2):145-61.