Opioid Research Seeks to Separate Analgesia from Addiction

Given the concerns with opioids, clinicians are increasingly considering alternatives in “multimodal” analgesia strategies, and referring patients with chronic pain to practitioners of complementary health approaches and biobehavioral treatments. Drug development programs are also seeking alternatives in compounds that meet the analgesic efficacy benchmark of opioids without their addictive liability.

“FIRST-IN-CLASS” NOVEL ANALGESICS RACE TO APPROVAL

The most recent investigational, novel opioid analgesic to meet efficacy endpoint measures in placebo-controlled phase 3 trials was described in a news announcement on March 20 as a first- in-class “full mu-opioid agonist molecule designed to provide potent pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids.”

The announcement by the analgesic’s manufacturer, Nektar Therapeutics, indicated that this investigational product, NKTR- 181, had been evaluated under the US Food and Drug Administration (FDA) Fast Track designation for the treatment of moderate to severe chronic pain. The manufacturer explained that although the investigational drug is a full mu-opioid agonist, it has low permeability across the blood-brain barrier and slow rate of entry into the brain, which is credited for attenuating the dopamine release that underlies the euphoria from opioids.

In a study comparing the abuse potential of 3 different dosages of NKTR-181 to 40 mg of oxycodone in 42 recreational, nondependent opioid users, published in the March 2017 issue of Pain Medicine, all doses of the investigational agent had significantly lower Drug Liking scores than the oxycodone comparator.2 The highest dose (400 mg) did demonstrate a higher Drug Liking than placebo, but the difference was characterized as small, and the onset was delayed compared with that of oxycodone.

On September 30, 2016, another pharmaceutical manufacturer, Grünenthal Group, released favorable phase 3 results regarding use of their investigational product, cebranopadol, in patients with cancer-related pain. This investigational agent is the first to act as an agonist at both the opioid and the nociceptin/orphanin FQ peptide receptors.

The phase 3 trial results, presented last September at the 2016 World Congress on Pain in Yokahama, Japan, described the outcomes of a double-blind, active-controlled, multiple-dose study with patients randomized to either once-daily cebranopadol or twice-daily morphine extended release. The investigators described it as one of the largest trials to be conducted in patients with cancer and indicated that cebranopadol demonstrated comparable efficacy to morphine.

The results of a study of the abuse potential of cebranopadol, presented in a poster at the 2016 PainWeek conference in Las Vegas, Nevada, compared the investigational agent in 200-mcg, 400-mcg, » and 800-mcg doses with hydromorphone 8 mg and 16 mg, and with placebo.3 Lead author Marta Sokolowska, PhD, of Grünenthal USA, and colleagues reported that the 200-mcg and 400-mcg doses did not separate from placebo on the abuse potential assessments and had responses lower than did hydromorphone. The responses to 800 mcg were generally similar to responses to hydromorphone 8 mg, but they were lower than responses to hydromorphone 16 mg, and they took approximately 3 hours to manifest compared with 1.5 hours for both dosages of hydromorphone.

PURSUING COMPOUNDS PAST THE MU-OPIOID RECEPTOR

Another first-in-class investigational analgesic (CR845/Cara Therapeutics) warrants that description for selectively acting on kappa-opioid receptors (KORs) outside the central nervous system while having no activity at the mu-opioid receptor. CR845 exerts the analgesic and anti-itch effects of a peripherally acting KOR agonist, but it does not cross the blood-brain barrier to promote the hallucinatory and dysphoric effects associated with central KOR activation.

The agent was administered intravenously in a phase 2 placebo-controlled trial in patients undergoing laparoscopic hysterectomy or bunionectomy procedures with favorable, albeit preliminary results.4 In a phase 2a study of 4 different oral dosages administered twice daily for 2 weeks to patients with osteoarthritis of the knee or hip, the 2 highest doses (1 mg and 5 mg) were associated with reduced pain scores, which the investigators characterized as “similar to those reported for other classes of analgesics used for the treatment of chronic pain in patients with osteoarthritis.”

Frédérique Menzaghi, PhD, of Cara Therapeutics, and col- leagues presented the results of the phase 2 study with the oral formulation, in addition to reporting on a separate human abuse liability trial, at the 2016 PainWeek conference. In the latter tri- al, 44 recreational, nondependent drug users were randomized in a 4-way crossover design to receive injections of therapeutic (5 mcg/kg) and supratherapeutic (15 mcg/kg) doses of CR845, placebo, and 0.5 mg/kg pentazocine (Talwin/Pfizer).

Menzaghi and colleagues indicated that the study design was validated by the significantly higher Drug Liking scores for pentazocine than placebo. The scores for CR845 were reported to be significantly lower than with pentazocine throughout an 8-hour observation period, with only “small elevations” relative to placebo, which were not dose-related.

ON THE HORIZON

Other promising candidate compounds are emerging from preclinical investigations, with a wide net being cast for possibilities. The scope of that search is reflected in a December 5, 2016, announcement of a collaboration for advanced research of targeted non-opioid, non-NSAID an- algesic compounds between Purdue Pharma, manufacturer of several prominent opioid products, including OxyContin and MS Contin, and AnaBios, proprietors of the Phase-X® discovery platform that “enables the discovery of novel drugs directly in normal as well as diseased human tissues, minimizing animal experimentation, maximizing the chances that preclinical data will successfully translate during clinical development.”5 Purdue described plans to develop its Nav1.7 sodium ion channel drug candidates, to act at the nociceptors at the end of pain-sensing nerves, close to the region where the pain impulse is initiated.

Don Kyle, PhD, of Purdue Pharma, commented in the release, “Through this unique collaboration we have tremendous opportunity to quickly advance new treatments into the clinic and potentially serve the many chronic pain patients who cannot find relief with existing medications.” ■

REFERENCES

1. NKTR-181 meets primary and secondary endpoints in phase 3 SUMMIT-07 study in chronic pain [news release]. San Francisco, CA: Nektar Therapeutics; March 20, 2017. prnewswire.com/news-releases/nktr-181-meets- primary-and-secondary-endpoints-in-phase-3-summit-07-study-in-chronic- pain-300425931.html. Accessed May 12, 2017.

2. Webster L, Henningfield J, Buchhalter AR, Siddhanti, et al. Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med. 2017 Mar 10. doi: 10.1093/pm/pnw344. [Epub ahead of print]

3. Eerdekens M,Sokolowska M, Nemeth R, Babich E, Szeto I. Cebranopadol: a novel first-in-class analgesic in development for chronic pain conditions— results from a human abuse potential study in non-dependent recreational opioid users. Paper presented at: Pain Week 2016; September 6-10, 2016, Las Vegas, NV.

4. Cara Therapeutics announces positive data from quantitative phase 1 trial measuringrespiratory safety of I.V. CR845 [news release]. Stamford, CT: Cara Therapeutics; April 24, 2017. globenewswire.com/news- release/2017/04/24/970161/0/en/Cara-Therapeutics-Announces- Positive-Data-From-Quantitative-Phase-1-Trial-Measuring-Respiratory-Safety- of-I-V-CR845.html. Accessed May 12, 2017.

5. Purdue Pharma and AnaBios collaborate to advance research for non-opioid, non-NSAID treatments for chronic pain [news release]. Stamford, CT and San Diego, CA: Purdue Pharma LP and AnaBios Corporation; December 5, 2016. purduepharma.com/news-media/2016/12/purdue-pharma-and-anabios- collaborate-to-advance-research-for-non-opioid-non-nsaid-treatments-for- chronic-pain-program-will-accelerate-purdues-nav1-7-sodium-ion-channel- drug-candidates-wit/. Accessed May, 12, 2017.