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Buprenorphine Offers Hope to Vets Who Suffer from PTSD, Pain, SUDs

April 12, 2016
Substance use disorder, including opioid use disorder, often goes hand in hand with chronic pain and PTSD among veterans. Treatment with a combination of buprenorphine/naloxone at a dose that is used to treat opioid dependency appears to help treat all 3 conditions.

Interview with Robert B. Raffa, PhD, and Ilene Robeck, MD

US veterans who served in Iraq and Afghanistan often suffer simultaneously from chronic pain, post-traumatic stress disorder (PTSD), and substance use disorders—including opioid use disorder.

 A new study has found that a combination of buprenorphine/naloxone (Suboxone) or buprenorphine alone (Subutex, since removed from the market) improved the overlapping symptoms of PTSD, pain, and opioid use disorder in veterans diagnosed with all 3 conditions.1Vietnam veteran Jim Alderman reacts during a therapy session for combat-related stress at the Bay Pines Veterans Affairs Medical Center in Bay Pines, Fla. Oct. 29, 2015. Alderman recently completed a seven-week inpatient post-traumatic stress disorder program for military veterans. DoD photo by EJ Hersom.

Buprenorphine/naloxone is FDA-approved for the treatment of opioid use disorder (Suboxone, Zubsolv, generic), while buprenorphine as an IV, transdermal, or buccal formula, is approved for the treatment of chronic pain (Buprenex, Butrans, Belbuca, generic). Note that the dose used to treat pain (contained in the patch or buccal medication) is lower than that used to treat opioid use disorder.

In the retrospective study, which included 382 Iraq and Afghanistan veterans in US Department of Veterans Affairs health care from October 1, 2007, to July 29, 2013, investigators compared PTSD symptom severity after 6 months of treatment with buprenorphine/naloxone or buprenorphine alone (n=177) with a similar group of veterans maintained on conventional (moderately high) opioid therapy (n=205).

The team found the positive effect on PTSD symptoms among the buprenorphine/naloxone-treated group, although modest, increased over time (after 8 months), without an increase in pain. In contrast, there was a nonsignificant trend toward worsening of PTSD symptoms with more time on traditional opioid therapy.

According to the study, twice as many veterans in the buprenorphine/naloxone group (23.7%) experienced improvement in PTSD symptoms compared to those in the opioid therapy group (11.7%)  (P=0.001). Compared to veterans in the opioid therapy group, veterans receiving buprenorphine showed significant improvement in PTSD symptoms after 6 months, with increasing improvement up to 24 months (incidence rate ratio = 1.79; 95%CI, 1.16–2.77; P=0.009). There were no differences in the longitudinal course of pain ratings between groups.

"I'm based at the VA, where we see this unfortunate triad of conditions in a lot of vets—particularly younger ones," said the study's lead author, Karen Seal,MD, MPH, Director of the Integrated Pain TeamandIntegrated Care Clinic for Iraq and Afghanistan Veterans, at the San Francisco VA Medical Center, and a professor at the University of California, San Francisco.

"We had hypothesized that patients with the combination of PTSD, chronic pain, and substance use disorders would show improvement when treated with buprenorphine/naloxonebecause of its neurobiology. I was gratified to see this in our results. It was a modest signal, and fit with our clinical observations," she told Practical Pain Management.

Dr. Seal noted, however, that "before we draw any conclusions, the next step is to conduct a full-scale, prospective, dedicated trial" to see if they observe similar results.

How Does Buprenorphine Work?

Experts can only speculate how buprenorphine/naloxoneworks on the trio of difficult to treat conditions. According to the study, "By acting on several different opioid receptors, buprenorphine may stabilize multiple neural circuits that mitigate pain and opioid craving (μ-opioid receptor), interrupt fear memory consolidation (nociceptin opioid receptor), and improve anxiety and depression symptoms (κ-opioid receptor)."

Robert B. Raffa, PhD, aprofessor at Temple University School of Pharmacy in Philadelphia, PA, offers this hypothesis. "Buprenorphinediffers from the other traditional opioids such as morphine and oxycodone, in having additional mechanisms of action, specifically, nociceptin/orphanin FQ (ORL-1), called the NOP mechanism."

The pharmacologist points to research illustrating that NOP levels went up when PTSD was induced in rats, while another study showed a NOP receptor antagonist inhibited that rise. "So it's kind of cool, and shows how buprenorphinecould be useful for treating PTSD," noted Dr. Raffa. "The fact that it takes several weeks to be effective, suggests it may not be the immediate reaction at the receptor, but the up or down regulation that accounts for the positive effect."

A Safer Alternative to Stronger Opioids

The study is particularly of note in the wake of the new CDC Guideline for Prescribing Opioids for Chronic Pain. Unlike full μ-opioid agonists, buprenorphine, as a partial μ receptor agonist, has less reward potential, and a ceiling effect, which makes it less likely to produce the same level of tolerance, physical dependence, and withdrawal symptoms as other full agonist opioids, noted the study authors.

Ilene Robeck, MD, Co Chair of the National VA PACT Pain Champions Initiative and Director of Virtual Pain Care for the Richmond VA in Virginia, has witnessed first-hand how effective buprenorphine can be for veterans with PTSD.

“Opioid use disorder and PTSD have overlapping symptoms that can be better addressed by effectively treating the opioid use disorder,” Dr. Robeck told Practical Pain Management. “By treating the opioid use disorder with buprenorphine/naloxone, we are better able to stabilize and treat PTSD.”

"Because of the risks of traditional opioid therapy, options like buprenorphine/naloxoneare going to become more widely studied," said Dr. Seal. "We have lots of patients in the VA with chronic pain and PTSD who don't want to be on opioids. Buprenorphine is potentially far safer for these patients, and also for those who suffer from opioid dependence."

And because the study suggests a mechanistic explanation for the findings, it should apply to anyone with PTSD, saysDr. Raffa. "The benefits of reduced pain and suicides, and better quality of life would be the same for everyone, not just veterans."

Access an Issue

Buprenorphine two formulas—Suboxone (buprenorphine/naloxone) and Subutex (buprenorphine, which has since been removed from the market)—were the first FDA-approved medications to treat opioid dependency to be prescribed or dispensed in physician offices, according to the Substance Abuse and Mental health Services Administration. Under the Drug Addiction Treatment Act of 2000 (DATA 2000), qualified physicians need a waiver in order to prescribe buprenorphine/naloxone, and once certified, there are limits on the number of patients they may treat: up to 30 the first year, and after that up to 100.

“If the positive effects of buprenorphine/naloxone result in the drug becoming more widely used, it may be difficult for patients to get a prescription,” said Ilene Robeck, MD, Co Chair of the National VA PACT Pain Champions Initiative and Director of Virtual Pain Care for the Richmond VA in Virginia. "There are a lot more patients who need it than there are doctors who're certified to dispense it.  It's important for us to address that resource disparity in this country now," said Dr. Robeck.

Dr. Seal's study might even open the way for the discovery of non-opioid PTSD medications that involve the NOP receptor system, said Dr. Raffa. "The study creates possibilities of what can be done for patients now, and what might be stimulated in terms of new drug discovery targets. You can't get much better than that."

Dr. Seal has declared that she has no financial interests relating to the article. Dr. Raffa has declared that he has no financial interests relating to the article. However, he does consult for a company that markets buprenorphine, although he gets no financial benefits from sales.

Last updated on: July 8, 2018

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