Amid all the negative publicity that has grown around opioid use in the United States, there are two separate developments that might just improve the odds of Avecho attracting a partner for its TPM opioid patches….
A popular view that has grown in America is that cannabis is the magic bullet that can solve the country’s opioid crisis. Most US states have now approved cannabis as an alternative to opioids for managing chronic pain. And opioid addiction itself is a qualifying condition for medical marijuana in New York, Pennsylvania, and New Jersey. (1)
But a growing body of evidence suggests that there is cause for concern.
Last year, the results of a four year prospective study of 1514 participants was published in The Lancet. The Australian study examined the effect of cannabis use in people with chronic non-cancer pain who were prescribed opioids. The authors reported finding no evidence that cannabis use improved patient outcomes. The cannabis users had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or exerted an opioid-sparing effect. (2)
In a second study, a systematic review of 12 longitudinal studies published in the Journal of Clinical Psychiatry in June last year, it was found that there was an association between greater cannabis use and poorer symptomatic outcomes in patients with wide-ranging anxiety and mood diagnoses. The 12 longitudinal studies in 11,959 patients with post-traumatic stress disorder, panic disorder, bipolar disorder and major depression were reviewed to determine the longer-term effects of cannabis use. For each disorder, most studies showed that cannabis users had more severe symptoms and lower rates of remission than less frequent users or nonusers. None of the studies suggested cannabis use might be a viable therapeutic strategy for anxiety and depression. The authors concluded that ongoing use of cannabis that is more than occasional would likely hurt therapeutic outcomes, and that reducing or ceasing use of cannabis would likely improve them. (3)
A further study published last July/August in the Journal of Addiction Medicine surveyed the confidential responses of 57,146 US household residents to gather reliable evidence on substance abuse in the United States. One of the study’s findings was that medical cannabis use was associated with more use and misuse of prescription opioids. (4)
Finally, this month, a new study has overturned the results of a widely-cited 2014 study published in JAMA Internal Medicine. The study had reported a nearly 25% lower average rate of opioid overdose deaths between 1999 and 2010 in those US states with medical marijuana laws. The 2014 study has since been cited in more than 350 scientific articles and has been widely seized upon by advocates, industry representatives and lawmakers as justification for further marijuana liberalization in the United States. As the number of US states with medical marijuana laws has grown to 34 since 2010 (perhaps partly due to the expectation that the opioid death toll would be lowered), Stanford University researchers decided to replicate the 2014 study and expand its analysis to include seven more years of data. When the study time frame was extended through to 2017, the association between medical marijuana laws and opioid overdose deaths reversed. Those states which had passed medical marijuana laws had a nearly 23% higher average rate of opioid overdose deaths. (5, 6)
My prediction is that there will be more studies providing further evidence that cannabis is not the simple solution to America’s opioid problem. It seems to me that the United States has not only failed to resolve its issues with opioid addiction and mortality, its lawmakers have now exacerbated the problem. Despite the introduction of the first abuse-deterrent opioid in 2010 (it and all subsequently approved ADOs are oral drugs) and despite the explosion of states which have approved cannabis as an alternative pain therapy to opioids, the stark fact is that drug overdose deaths in the US rose from ~38,000 in 2010 to more than 79.000 in 2017 (last available figures). (7)
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Almost a year ago the FDA said that it would withdraw its guidance for developing new analgesic drugs and issue new guidance in 2019.
Last week, that FDA draft guidance for new analgesic opioids was released. The draft guidance document describes information that the FDA will be requesting of drug sponsors to enable it to evaluate benefits and risks of any proposed new opioid relative to already-approved analgesics. The agency will be looking for characteristics which may increase or decrease the risk of misuse, abuse, opioid use disorder, overdose or accidental exposure. Sponsors will need to demonstrate that their product has advantages over currently available options.
Some of the questions that the FDA says it will consider are
Does the drug have characteristics that mitigate adverse events associated with opioid analgesic drugs, including respiratory depression, sedation, and constipation?
Does the drug have characteristics that mitigate the risk of opioid use disorder when used as labeled?
Do the formulation and/or excipients pose risks to patients?
Are there characteristics of the drug that increase or decrease the risk for respiratory depression, sedation, or development of opioid use disorder in patients (e.g., large residual opioid in transdermal systems, high dosage strengths)?
Does this analgesic drug offer any advantages relative to available approved analgesic drugs for each indication, with regard to effectiveness or duration of response?
Does this analgesic drug offer any other safety advantages or disadvantages relative to available approved analgesic drugs for each indication ?
The agency is also considering whether pre-approval incentives are warranted to foster the development of new therapies, either opioid or non-opioid, to treat pain. (8, 9, 10)
In January, AVE received the final minutes of its Pre-IND meeting with the FDA for its 3-day TPM /Oxymorphone patch, which was conducted in December last year. The FDA agreed at the meeting that the 505(b)(2) pathway remained a feasible path for approval and that a broad chronic indication/label similar to that granted to Opana ER was potentially achievable. It also suggested some additional studies for consideration, that could potentially enable the patch to gain valuable abuse deterrent label claims.
Then-CEO, Ross Murdoch, stated that the approvability of a novel opioid patch in the USA had been questionable in the mind of potential partners. The positive outcome from the Pre-IND meeting with the FDA was said to have provided further confidence in AVE’s blueprint for moving forward. I would expect that the FDA’s new guidance for opioid analgesics will add to that confidence.
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