Opioid Use Disorder

Key Insights

• Opioids such as oxycodone and morphine are generally prescribed to treat pain. However, the potency and effects of these drugs mean they have a high potential for abuse. Over the 12 months ending in 2021, over 75,000 deaths were attributed to opioids in the U.S.
• While the nature of opioids renders them highly addictive, socio-political forces over the past number of years have contributed to a so-called Opioid Crisis in the U.S. treatments remain ineffective, and there remains a reluctance to adopt evidence-based harm reduction strategies despite increasing deaths.
• Psychedelics are under exploration as novel therapeutics for treating opioid use disorder. One of the most researched for this specific substance use disorder is ibogaine. Despite its cardiac safety profile, ibogaine has alleviated withdrawal symptoms and reduced cravings.

Opioid Use Disorder

Opioids are a class of naturally occurring drugs that medical professionals generally prescribe to treat moderate to severe pain. This class of drugs includes morphine, codeine, oxycodone, heroin, and fentanyl, all of which act on opioid receptors in the brain. The potency of these drugs results in their ability to instil a sense of euphoria once consumed, and consequently, people can easily misuse opioids.

Misuse of these pain relievers often leads to dependency and addiction, overdose incidents, and deaths [1]. The DSM-V classifies this form of substance use disorder as opioid use disorder (OUD), which entails the persistent desire or unsuccessful efforts to cut down or control opioid use [2]. While anyone around the globe can misuse opioids, OUD has become particularly prevalent in the U.S.

Over the past twenty years, the prevalence of chronic pain in the U.S. has resulted in a drastic increase in the use of opioids as a method to treat and manage chronic pain. Consequently, there has been a simultaneous increase in people misusing opioids, both prescription and non-prescription. In 2011, the Centers for Disease Control (CDC) declared overdoses from prescription painkillers, including opioids, an epidemic [3].

Now, accidental drug overdose from opioids is one of the leading causes of death in Americans under 50 [4]. Moreover, over 12 months ending in April 2021, an estimated 100,306 drug overdose deaths happened in the U.S., 75,673 of which were attributed to opioids [5].

What causes Opioid Use Disorder?

Several risk factors for developing OUD exist and patients should be assessed for these factors before beginning treatment with opioids. Some of these risk factors include a personal or family history of substance misuse, poor social support, a history of trauma, and underlying mental health issues [6]. While these factors can contribute to developing OUD, people often begin misusing opioids through no fault of their own.

Initially, people may be prescribed certain opioids by a medical professional to assist them with pain management. By taking opioids repeatedly over time, your body develops a tolerance to the euphoric effects opioids can instil. Many people who develop such tolerance may feel the need to increase their doses to continue to feel the euphoric effects which in turn increases their tolerance.

Medical professionals may refuse to increase a person’s doses due to the known risks of dependence. At this point, a person who was initially prescribed opioids to help better manage their pain may turn to illegally obtained opioids while simultaneously using methods different from what was prescribed, such as crushing a pill so that it can be snorted or injected [7].

The prevalence of OUD has been exacerbated in the U.S. for various reasons. Regulatory failures, the liberalisation of laws governing the prescribing of opioids and aggressive marketing strategies from pharmaceutical companies are just some of the reasons for the rise in opioid misuse [8].

The use of opioids in pain management has a unique history in the U.S. This class of drugs initially entered the market in the mid-1990s with the particularly infamous oxycodone, manufactured by Purdue Pharma. Purdue Pharma and other companies promoted their opioid products by heavily lobbying lawmakers, sponsoring continuing medical education courses, and funding professional and patient organizations, amongst other things. During all of these activities, they emphasized the safety, efficacy and low potential for addiction to prescription opioids [9].

Many medical professionals did not question this information and instead saw opioids as an effective tool for pain management. Furthermore, the healthcare system in the U.S. allowed for the incentivization of prescription practices which significantly increased the number of opioids they prescribed. In 2017, these failures were recognized when the President’s Commission on Combatting Drug Addiction and the Opioid Crisis found that the opioid crisis was partly caused by “inadequate oversight by the Food and Drug Administration” [10].

Despite acknowledging these failures and holding Purdue Pharma somewhat accountable for their role in the opioid crisis as they continue to appear in court for their actions, much remains unchanged. Death related to opioid overdose continues to increase in the U.S. while treatment options for OUD are limited.

Treating Opioid Use Disorder

Similar to other substance use disorders, there is no generally effective treatment for OUD. Treatment usually consists of medication-assisted therapy. As a person increasingly misuses opioids, their body becomes dependent on the drugs. The resulting physiological changes mean that a person often experiences withdrawal symptoms from the abrupt discontinuation of opioid use. Withdrawal symptoms can be both physical and psychological, and treating these symptoms can improve the patient’s health and facilitate their participation in a rehabilitation program [11].

Treating OUD often begins with medically supervised withdrawal or detoxification. Several medications are used at this stage to help patients transition from physical dependence on opioids. Methadone or buprenorphine are usually the first point of call and are given in gradually decreasing doses to taper a person off opioid use [12]. In some cases, these medications are used in tandem with behaviour therapy. However, these medications have somewhat limited efficacy as many patients receiving these treatments quickly relapse and return to using opioids [13].

Harm reduction strategies are imperative when discussing OUD due to the highly addictive nature of opioids and the subsequent relapse rates. Harm reduction incorporates a spectrum of strategies that includes safer use, managed use, abstinence, and addressing conditions of use and the use itself [14].

In terms of OUD, Naloxone is a vital medication necessary for reducing the harm caused by opioids. Naloxone can be used in an emergency when respiratory arrest due to an opioid overdose has occurred or is imminent. Naloxone flushes out receptors and can reverse the overdose but is not a form of OUD treatment [12].

A crucial part of harm reduction is acknowledging that people use drugs for various reasons. Providing space for safer use or the managed use of a drug decreases the harms associated with that drug, particularly for people who inject drugs. For example, supervised injection centres and needle exchanges reduce the likelihood of overdose and the transmission of diseases such as HIV via the sharing of needles [15].

Despite harm reduction strategies and currently available medications for OUD, there is an unmet need when treating OUD. As a result, researchers continue to search for more effective treatments, with some turning their attention to psychedelics as novel potential treatments for OUD.

Psychedelics and Opioid Use Disorder

OUD is a form of substance use disorder (SUD). Given that many psychedelics are showing significant potential in treating various SUDs, these drugs and the mechanisms through which they act may apply to OUD.

To find out more about how psychedelics are being used to treat SUDs, check out our previous article. In this previous article, we explore some of the history underlying psychedelics and SUD, the potential of psychedelics, including psilocybin, MDMA, ketamine and ibogaine, and their potential mechanism of action.

In terms of OUD, the highly prevalent nature of OUD has led some researchers and companies in the psychedelic space to target OUD specifically. Here we will detail some of the key compounds under investigation, the critical studies on this topic and the companies leading these efforts.

The largest survey study to date on this topic used data from the U.S. National Survey on Drug Use and Health (2015–2019) (N = 214,505) to assess the association between psychedelic use and opioid use disorder (OUD). Lifetime psilocybin use was associated with lowered odds, while no other substances, including other classic psychedelics, were associated with lowered odds of OUD.

A recent longitudinal study assessed data from three ongoing open, prospective cohorts of people who use drugs (PWUD) in Vancouver, Canada, to investigate the relationship between psychedelic use and daily opioid use. Upon analysis, it was found that classic psychedelic use in the last six months was associated with 55% reduced odds of everyday opioid use.

Ibogaine

One of the major psychedelics under investigation for the treatment of OUD is ibogaine. Research exploring the anti-addiction properties of ibogaine dates back to the 1990s, and many clinics offering ibogaine treatment exist in countries where ibogaine remains somewhat legal such as in Mexico. Some clinical trials have explored the potential of ibogaine in treating OUD.

A 2017 study in New Zealand, where ibogaine is legal, found a single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months.

An observational study involving people seeking addiction treatment at a private clinic (n=30) found that ibogaine was associated with substantive effects on opioid withdrawal symptoms for up to one month or even 12 months in select individuals.

Another study (n=50) investigated the efficacy of ibogaine (1.26 – 1.4g/70kg) in treating withdrawal symptoms amongst patients with opioid use disorder. At 48 hours following ibogaine administration, 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range.

Despite these positive effects, it must be noted that ibogaine administration can lead to specific adverse effects. One of the major effects ibogaine has on the cardiovascular system is the prolongation of the Q.T. interval, the time it takes for the heart chamber to contract and subsequently relax, which can increase a person’s risk of cardiac arrhythmia [16].

A trial (n=27) evaluating the safety, tolerability, and pharmacokinetics of noribogaine (an ibogaine derivative) at 60, 120, or 180mg/70kg administered to opioid-dependent patients withdrawing from methadone found that noribogaine was well tolerated across the entire dose range. Noribogaine was also associated with a trend toward decreased total score in opioid withdrawal ratings, although this trend was statistically nonsignificant. Importantly, the ascending noribogaine dose was correlated with the prolongation of heart contractions (longer Q.T. intervals) to the degree that would be concerning in a clinical setting. Such findings indicate ECG monitoring to enable dose adjustment or discontinuation to mitigate cardiovascular risk in future studies.

Psychedelic Companies and Opioid Use Disorder

MindMed is one of the largest companies in the psychedelics space and is developing various psychedelics for mental health disorders. In addition to exploring the efficacy of LSD for treating anxiety and microdoses of LSD for adult ADHD, MindMed is also researching 18-MC for opioid withdrawal & addiction. 18-MC is based on ibogaine but has been synthesized to be non-hallucinogenic while still having ibogaine’s anti-addiction properties. The company’s trial with 18-MC is now moving to Phase II of the clinical trial process.

Through its DemeRx subsidiary, atai Life Sciences is developing ibogaine and noribogaine to treat OUD. In March 2021, DemeRx received approval from the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to launch a Phase I/IIa trial exploring the safety and efficacy of ibogaine hydrochloride (DMX-1002) for the treatment of OUD. The trial will first explore the effects of DMX-1002 in recreational drug users before commencing the second stage of the trial in those with OUD.

Gilgamesh Pharmaceuticals is developing various ibogaine analogues for the treatment of OUD. The company has recently partnered with Columbia University to investigate and develop its extensive library of ibogaine analogues. Gilgamesh hopes to name a lead candidate with an improved cardiac safety profile for clinical trials later in 2022.

The Canadian company, Universal Ibogaine, aims to treat OUD using ibogaine. The company operates a treatment centre in Mexico and has administered more than 3,500 treatments with ibogaine to date. Universal Ibogaine hopes to develop a network of substance use treatment clinics in Canada and beyond upon regulatory approval.

Ultimately, psychedelics hold promise for treating OUD and other substance use disorders. However, further research is needed before these treatments reach people in need. In the meantime, focusing efforts on the various harm reduction strategies is imperative to address the ongoing opioid crisis.

References

1. National Institute on Drug Abuse. (n.d). Opioids. National Institute of Health. https://nida.nih.gov/drug-topics/opioids

2. Hartney, E. (2020). Opioid Use Disorder in the New DSM-5. Verywell Mind.https://www.verywellmind.com/opioid-use-disorder-22046

3. SHADAC. (n.d). The Opioid Epidemic in the United States. The State Health Access Data Assistance Center. https://www.shadac.org/opioid-epidemic-united-states

4. Drug Policy Alliance. (2018). Drug Overdose. New York: Drug Policy Alliance. https://drugpolicy.org/issues/drug-overdose

5. Centers for Disease Control. (2021). Drug Overdose Deaths in the U.S. Top 100,000 Annually. Centers for Disease Control. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm

6. Webster, L. (2017). Risk Factors for Opioid-Use Disorder and Overdose. Anesthesia & Analgesia. https://doi.org/10.1213/ane.0000000000002496

7. Mayo Clinic. (n.d). How opioid addiction occurs. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/prescription-drug-abuse/in-depth/how-opioid-addiction-occurs/art-20360372

8. Manchikanti, L., Helm, S., Fellows, B., Janata, J., Boswell, M., & Grinder, J. (2012). Opioid epidemic in the United States. Pain Physician, ES9-38. https://pubmed.ncbi.nlm.nih.gov/22786464/

9. DeWeerdt, S. (2019). Tracing the U.S. opioid crisis to its roots. Nature. https://www.nature.com/articles/d41586-019-02686-2

10. Kolodny, A. (2020). How FDA Failures Contributed to the Opioid Crisis. AMA Journal of Ethics. https://journalofethics.ama-assn.org/article/how-fda-failures-contributed-opioid-crisis/2020-08

11. Schuckit, M. (2016). Treatment of Opioid-Use Disorders. The New England Journal of Medicine. https://doi.org/10.1056/nejmra1604339

12. Johns Hopkins Medicine. (n.d). Treating Opioid Addiction. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/opioids/treating-opioid-addiction.html

13. Coffa, D., & Snyder, H. (2019). Opioid Use Disorder: Medical Treatment Options. American Family Physician. https://www.aafp.org/afp/2019/1001/p416.html

14. National Harm Reduction Coalition. (n.d). Principles of Harm Reduction. National Harm Reduction Coalition. https://harmreduction.org/about-us/principles-of-harm-reduction/

15. Ng, J., Sutherland, C., & Kolber, M. (2017). Does evidence support supervised injection sites? Canadian Family Physician. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685449/

16. Koenig, X., & Hilber, K. (2015). The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules, 20(2), 2208-2228.