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Meeting Highlights

American Academy of Pain Medicine 2016

Walter Alexander

The 32nd Annual Meeting of the American Academy of Pain Medicine brought together approximately 1,000 clinicians and other professionals in Palm Springs, California, from February 18 to 21. Meeting highlights included sessions on the abuse potential of benzhydrocodone; a low-cost opioid taper program; and an abuse-deterrent formulation of hydrocodone.

Oral Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone

  • Sven Guenther, PhD, Executive Vice President of Research and Development, KemPharm, Inc., Coralville, Iowa

A novel prodrug of hydrocodone in combination with acetaminophen (KP201/APAP) leads to lower hydrocodone exposure and as a consequence may have reduced abuse potential and overdose risk. In the prodrug benzhydrocodone, hydrocodone is chemically bound to benzoic acid, according to Dr. Guenther. After oral administration, release of hydrocodone through breaking of the covalent bond occurs most rapidly and efficiently in the intestinal tract. KP201 has shown decreased bioavailability at abuse levels after oral intake and after insufflation (snorting).

KemPharm conducted a single-center, randomized, double-blind, active- and placebo- controlled clinical trial among non­addicted recreational opioid users. The study (KP201.A01) was designed to compare abuse liability and relative bioavailability and safety of oral KP201/APAP (6.67 mg/325 mg per tablet) compared with oral hydrocodone bitartrate with acetaminophen (HB/APAP) (7.5 mg/325 mg per tablet). Opioid combination products containing HB are the second-most commonly prescribed drugs in the U.S.,1 Dr. Guenther said.

Subjects received seven individual treatments separated by washout periods, including a placebo period and periods with low, mid, and high doses of each agent. There were 62 completers (mean age, 29.1 years) out of 151 enrolled subjects.

Analysis showed that with up to four tablets, KP201/APAP mean plasma hydrocodone concentrations (single oral dose) were bioequivalent to HB/APAP, a currently marketed hydrocodone combination product. “That means you have the same analgesia, the same efficacy and safety profile when you take KP201/APAP orally as intended,” Dr. Guenther said. At 12 tablets, however, cumulative hydrocodone exposures at intervals between one and 24 hours post-dose (AUC0–1 through AUC0–24) were reduced by about 15.8% to 4.8% (P = 0.0102–0.0324) for KP201/APAP. In addition, peak hydrocodone exposure (Cmax) was reduced by about 10.0% (P = 0.0333) and 11.5% (P = 0.0134) following oral doses of eight and 12 tablets of KP201/APAP, respectively, when compared to equivalent doses of HB/APAP.

Furthermore, at mid-dose (eight tablets), reductions of 20% or more in Cmax and AUC0-1 (measures of hydrocodone exposure) were observed in approximately 39% and 38% of the subjects, respectively, for KP201/APAP versus HB/APAP. At the high dose (12 tablets), approximately 25% and 34% of the subjects had a reduction of at least 20% in Cmax and AUC0–1, respectively, when comparing KP201/APAP with HB/APAP. The lower exposure, Dr. Guenther said, may potentially reduce the risk of oral overdose in this large patient population. “Also, it might buy you some extra time with someone who took too many pills,” he said.

In an earlier trial (KP201.A03) of insufflated KP201 (as active pharmaceutical ingredient powder without APAP), the reduction in peak hydrocodone exposure was about 36% compared with HB (also dosed without APAP). The cumulative exposure differences were even greater at early time points, with reductions ranging from about 95% to 56% from five minutes through two hours post-dose. Time to peak hydrocodone exposure (Tmax) was significantly delayed for KP201 versus HB (1.75 hours versus 0.50 hours). Both speed of onset and magnitude of effect correlate, Dr. Guenther noted, with behavior reward. The intranasal trial showed significantly lower drug liking and pupil dilation and greater difficulty for snorting with KP201 than with HB.

“The greater advantage for KP201/APAP,” Dr. Guenther said in an interview, “is in its deterrent characteristics among abusers who take hydrocodone products intranasally.” Adolescents are more likely than adults to abuse hydrocodone intranasally. They often also know how to extract APAP from hydrocodone/APAP formulations. If they “snort” extracted KP201, however, they inhale the inactive prodrug and actually get much less hydrocodone. “This might prevent them from escalating their euphoric experience—and hopefully, they lose interest,” Dr. Guenther said.

KP201 has been granted priority review by the Food and Drug Administration and has a PDUFA date in June 2016.

Boots on the Ground in Opioid Tapering: A Low-Cost, Medically Supervised Opioid Taper Program for Community-Dwelling Patients

  • Richard L. Stieg, MD, MHS, Aurora, Colorado, and Beth D. Darnall, PhD, Associate Clinical Professor, Stanford University School of Medicine, Stanford, California

A low-cost, 16-week opioid tapering program administered by a private physician and two assistants led to opioid reductions of 25% to 100% in 75% of patients, without significant changes in pain or psychosocial outcomes.

The program was developed by Dr. Steig, a neurologist and addiction specialist with extensive experience supervising pain clinics in academic and nonacademic settings. Dr. Steig, in an interview, first cited the drastic reduction in available multidisciplinary pain clinics over the last 25 years, and then three additional stimuli for his creation of the program: He read a book by Dr. Darnall (who led the present study) that impressed him deeply;2 he was planning on retiring from his practice; and he was looking for a new way to help people taper down or completely eliminate opioids in a cost-effective way.

Dr. Steig invited 119 patients to participate in a voluntary opioid taper program with two orientation sessions (groups of eight to 12 patients). At the talks, he notified them of his intent to retire and described the free program (except for the copays for their four monthly visits). “I told them that access to opioids was getting tougher and tougher, that insurance companies were bowing out of paying, and that doctors were declining to prescribe them—all good reasons to taper down,” Dr. Steig said.

Patients’ mean age was 47 years, with a mean of seven years on opioids, mean pain scores of 5.9 (on a 0–10 scale), and mean Morphine Equivalent Daily Doses of 244. The 48 patients who enrolled in the program each received a free copy of the book and a slow, individualized taper schedule. In the event of withdrawal symptoms, they were given pharmacological support (nonbenzodiazepine). Dr. Steig said that he had intended to provide psychosocial support as part of the program, but insurance coverage could not be secured for that component.

A surprising finding beyond the high success rate was that neither the baseline dose nor the duration of opioid use correlated with success. Analysis revealed significant improvement at 16 weeks among the 34 completers (13 remain in progress; one discontinued) in absolute change in opioid dose (P = 0.002) and in pain catastrophizing (P = 0.01), a measure of exaggerated mental and emotional response to pain. While 50% of the group reduced their opioids by 50%, 30% reduced them by 75% to 100%, and about 75% reduced doses by 25% to 100%. Dr. Steig noted that many of the subjects have continued to taper their doses after the 16-week study period.

“Success was totally dependent on self-motivation except for the little bit of coercion I provided in telling them I was retiring and that their health plan might cut them off. That’s the essence,” Dr. Steig said.

A strong trend (P = 0.055) was observed showing that opioid reductions were related to pain reduction, Dr. Darnall said in an interview. While more patients are needed in the ongoing study to lend greater statistical power, “the preliminary story is that people who taper opioids appear to have reductions in pain.” Pain catastrophizing at four months was also greatly reduced, she said. “The voluntary nature of the taper likely confers a high degree of controllability. In the end, two of our most important findings may be:

  1. Offer a taper pathway. Many patients will accept it.
  2. Make it voluntary and supportive so they know they are in control. It will reduce stress, and they are more likely to succeed.”

Efficacy and Safety of Hydrocodone Extended-Release Tablets Formulated With an Abuse-Deterrent Technology Platform for the Treatment Of Moderate-to-Severe Pain in Patients With Chronic Low Back Pain

  • Richard Malamut, MD, Head of the Pain Therapeutic Area for Teva Pharmaceutical Industries, Frazer, Pennsylvania

In a phase 3 trial assessing efficacy and safety, patients with histories of moderate-to-severe chronic low back pain for three months or longer receiving an oral hydrocodone bitartrate extended-release (ER) tablet formulated with CIMA abuse-deterrent technology experienced more effective alleviation of pain compared with placebo with a safety profile consistent with other opioids. The formulation (CEP-33237, Teva) resists tampering (e.g., crushing, chewing, dissolving in alcohol or water) that leads to rapid release of hydrocodone (dose dumping) and increased toxicity and side effects.

Patients entering the study were already receiving analgesia and had pain that was not well controlled, with average pain intensity (API) scores averaging above eight of 10. Subjects required around-the-clock treatment. An open-label titration period identified an optimal pain-relief dose without unacceptable adverse events.

In total, 371 patients (mean age, 51.8 years; 49% male) achieved an analgesic dose of hydrocodone ER (30 mg to 90 mg every 12 hours) and were randomized to a 12-week, double-blind, placebo-controlled, randomized-withdrawal treatment period. The primary endpoint was change from baseline to week 12 in the weekly average of daily worst pain intensity (WPI) scores on an 11-point scale.

In the withdrawal period (among patients randomized to placebo), “pain intensity started to inch up,” Dr. Malamut said in an interview. The least squares mean change in WPI from baseline at week 12 was significantly higher with placebo compared with hydrocodone ER (0.55 [0.14] versus –0.03 [0.12], P < 0.001). The percentage of patients with an API increase of 30% or more from baseline and an API score of 5 or greater at week 12 was significantly lower in the hydrocodone ER group (13%) than in the placebo group (19%) (P = 0.029). The percentage of patients with loss of efficacy (i.e., discontinuation for lack of efficacy [a secondary efficacy measure]) was lower with hydrocodone ER (23%) than placebo (30%): hazard ratio, 0.68; 95% confidence interval, 0.45–1.01; P = 0.059.

Rescue medications (hydrocodone immediate release), allowed in both groups, were used at the same level in both groups.

Common adverse events with hydrocodone ER during double-blind treatment were constipation (14%) and nausea (10%). No clinically meaningful differences in pure tone audiometry were observed between the two groups.

Dr. Malamut also noted that in a separate presentation of study data, study drug loss and diversion rates were low, supporting the potential abuse-deterrent properties of this formulation. “These results confirm that hydrocodone, even with the abuse-deterrent characteristics and the ER formulation, functions as an analgesic,” he said.


  1. Anson P. US hydrocodone prescriptions dropping. Pain News Network, April 14, 2015.
  2. Darnall B. Less Pain, Fewer Pills. Boulder, Colorado: Bull Publishing; 2014.
Author bio: 
The author is a freelance writer living in New York City.