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“Blended” Therapy: A Novel Approach to Reduce Opioid Use

Could a compounded formula using codeine lower patients’ overall opioid doses?

with Dennis Bonner, MD, and Courtney Kominek, PharmD, BCPS, CPE

Could a combination of codeine, hydroxyzine, and other medications help patients with chronic pain conditions lower their opioid intake? Yes, said Dennis Bonner, MD, physical medicine and rehabilitation physician at St. Mary Medical Center in Langhorne, PA, who presented his theory and study abstract at the 2018 Academy of Integrative Pain Management Global Pain Summit.

His compounded formula, known as LoMed (Levittown, PA), consists of codeine, Vistaril (hydroxyzine), gabapentin, ondansetron, and Colace. He is currently using the compound with about 50 patients and has submitted his product for patent, hoping that, “This methodology will get patients down to a safe MME without causing increased pain or withdrawal.”

A compounded formula using codeine could lower patients’ overall opioid doses, according to one doctor's novel research. (Source: 123RF)

From Concept to Action: Efforts to Limit High-Dose Opioid Prescriptions

Like many states, Pennsylvania, where Dr. Bonner practices, has had a significant opioid problem.2In 2017, the state had the third highest rate of death due to drug overdose.3 When thinking about ways to help his patients reduce their opioid intake, Dr. Bonner recalled that his aunt used to mix Vistaril (an antihistamine that is indicated as a sedative and to treat anxiety)4 with her pain medication to make it “work better.” He soon theorized that if hydroxyzine enhanced the effects of opioids, a combination of the two might also provide effective pain relief at lower opioid doses.

Research on the efficacy of hydroxyzine-opioid combinations for pain relief, however, has been limited and much of it dates back to the 1980s. One 1980 double-blind, single-dose study of 82 post-operative patients found that a combination of hydroxyzine and morphine offered more pain relief than morphine alone,5 and a 1983 double-blind study of 30 cancer patients noted that 100 mg of hydroxyzine IM provided longer-lasting pain relief than meperidine 50 mg IM.6 However, a 1990 paper noted that “the data do not confirm the purported clinical benefits of hydroxyzine-opioid combinations in comparison with appropriate regimens of opioids alone.”7 More recently, researchers have found that hydroxyzine, when administered along with other medications, may help patients reduce their use of opioids.8,9

Dr. Bonner decided to combine codeine with hydroxyzine, as it is one of the most commonly prescribed opioids and has one of the lowest MMEs per milligram; according to PPM’s opioid conversion calculator, 10 mg of codeine IM is the equivalent of just 1.0 mg of morphine IM.10 The maximal dose of codeine is 360 mg a day, or 54 MME.11

Dr. Bonner’s formula includes the following FDA-approved medications:

  • 60 or 120 mg codeine
  • 100 mg hydroxyzine
  • 300 mg gabapentin to prevent seizures
  • 4 mg ondansetron for nausea and vomiting
  • 100 mg docusate sodium for constipation.

After some of his in-office patients reported reduced pain, no side effects, and no withdrawal symptoms when using this combination, he recruited 20 patients for a small study.

Patient Feedback

In the study, patients came to Dr. Bonner’s office to report their pain level on a scale of 1 to 10 12 hours after their last dose of their usual pain medications. They were then given the first of three daily doses of LoMed; patients on opioids with an MME of 180 or higher received the 120 mg of codeine formula, and patients on opioids with less than 180 MME received the 60 mg formula. LoMed is taken three times a day (it has a maximum MME of 54). Patients also took their usual breakthrough pain medications (generally 15 mg oxycodone, four times a day, equivalent to 90 MME).

Patients were monitored for adverse reactions, and then discharged, before returning the next morning for follow-up. Fourteen subjects reported less pain on LoMed, while another five reported about the same level of pain as with their usual, higher doses of opioids. Just one patient reported increased pain, and required the higher codeine dose. Two outliers:

  • One patient on 180 MME a day reported their pain at a 4. With LoMed 60 mg, the patient took 117 MME a day, and reported their pain level at 0 to 1.
  • One patient on 330 MME a day reported their pain at a 7. The following day, on 144 MME a day, the patient reported a pain level of 4 to 5.

Some patients also reported increased mental clarity and better sleep, although some reported fatigue when they started the program. Although a very small sample size, Dr. Bonner’s statistical analysis determined that LoMed was effective for relief of pain and withdrawal symptoms.12

Monitoring Patients

After one year, all of the patients in Dr. Bonner’s original study have remained on, or returned to, the LoMed. An additional 30 patients have joined the LoMed program. Dr. Bonner says he sees these pain patients once a month and they undergo drug monitoring every quarter. Corrective measures are taken when needed for regulatory guidelines. As of January 2019, he also offers his LoMed patients access to LifeWIRE, a digital health monitoring program developed by Howard Rosen, MBA.13 LifeWIRE requests patient feedback on pain levels, symptoms, and mood via their Smartphone—every other day during the first week, and twice a week thereafter. About 15 LoMed patients have opted in so far.  When the app shows that a patient has not picked up their medication, is experiencing severe withdrawal or side effects, or shows signs of depression, Dr. Bonner makes an appointment to see them.

Overall, Dr. Bonner said he was very pleased with his patients’ response to LoMed. “We were expecting at least a 15% failure rate,” he noted, since a significant number of patients do not respond well to codeine.14 However, “In our experience, only people on high dose fentanyl (100 mcg or more a day) have difficulty converting” to LoMed. And although patients reported fatigue when they started the program, “all 50 are doing well, and the pain is well controlled.”

To prevent adverse reactions, Dr. Bonner advises that potential LoMed patients undergo a sleep study to test for sleep apnea as codeine, like all opioids, may depress the respiratory drive. He also advises pharmacogenetic testing in advance to predict any potential negative responses to LoMed ingredients. Potential patients should also undergo an electrocardiogram (EKG)as Zofran may increase the risk of arrhythmias15 and have a basic metabolic panel done.16 “Doctors should proceed with caution,” Dr. Bonner advised. “This is a powerful opioid, and should be monitored by a physician.”

Promising, but Not Quite There

While Dr. Bonner’s work is intriguing, Courtney Kominek, PharmD, BCPS, a clinical pharmacy specialist at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, MO, is skeptical. In her evaluation of Dr. Bonner’s study, Dr. Kominek noted that, “the blended therapy was started 12 hours after stopping former meds. Some of those opioids are long-acting, so much of that medication might still have been in their systems, and they might not have been experiencing withdrawal.”

She also pointed out several other problems with the study: “It wasn’t a randomized double-blind trial, and had a small number of patients. Plus, they only checked the pain scores one time after leaving the clinic.” With the addition of LifeWIRE, some patients are now providing more regular feedback on pain levels.

With regard to the use of hydroxyzine to enhance the analgesic effects of codeine, Dr. Kominek said, “Studies on Vistaril are pretty old, and it is not commonly prescribed, at least not in my practice. It is not typical to use Vistaril for pain.”

“His theory behind the cocktail is the principal of rational polypharmacy,” Dr. Kominek continued. “We prescribe medicines that work in different ways in hopes that we can capitalize on different mechanisms of action to relieve pain, while limiting opioid doses. I can appreciate the principle behind combining multiple meds,” but the flawed study design makes her doubt the efficacy of the program.

She added that, “Blended therapy isn’t something I’ve ever used, nor am I likely to. Most of the time, when working with patients on high levels of opioids, I typically will make small adjustments in their dose over long periods of time, so typically they don’t have changes in side effects or withdrawal symptoms. If someone were to come to me on high doses of opioids, standard practice, at least for me, would be a slow taper.”

As an example, Dr. Kominek described that a patient on a fentanyl 50-mcg patch, with no safety or substance use disorder concerns, would be reduced to 37.5 mcg from one to several months, then reduced again by another 12 micrograms.

Finally, moving patients from one opioid to another can be risky, since “there is no one standard conversion method” for MMEs, as Dr. Kominek pointed out. “MME calculators vary and doctors may choose to use different ratios in determining MME equivalents.”

While PPM, the CDC, and others offer conversion guides, several critics have pointed out that, “MME dosing was designed in an attempt to examine opioids with similar analgesic effects and should not be used to determine an exact mathematical dosing conversion. The pharmacology and unique properties of each opioid and patient individuality must be considered when a therapeutic opioid conversion is contemplated.”17

Time will tell whether Dr. Bonner’s formula proves effective on a larger scale and in the longer term.

Dr. Bonner reported no disclosures.

Last updated on: February 13, 2019
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New Opioid Program Raises Concerns for Chronic Pain Patients
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