Exploring the Mechanism of Maintenance Therapy
Updated: Apr 27
Over the past few decades, much has been revealed about opioid dependence that has shaped our comprehension of addiction as a chronic disease. Opioid drugs activate specific opioid receptors (mu, kappa, and delta in the spinal cord and GIT system. Initially, when heroin or other opioids derivatives are consumed, activation of these receptors in the human body induces euphoric effects. Subsequent doses will quickly lead to tolerance – the need for increasingly higher doses to produce the same effect – and physical dependence. Currently, the studies reveal that tolerance is a result of a reduction in either the number or the responsivity of opioid receptor
What are Opioids?
Opioids are a class of drugs naturally occurring in the opium poppy plant and that act on the endogenous receptors in the human body to produce a variety of effects, including the relief of pain, euphoria and GIT effects.
What do opioids do?
The opioid drugs, characterised by morphine, can potentially produce profound analgesia, physical dependence, mood changes, tolerance along with a hedonic ('rewarding') effect which may lead to dependence or compulsive drug use. The receptors for opioids are found both in the central and peripheral nervous systems. Within the central nervous system, opioid receptors are widely spread in the spinal cord. In the peripheral nervous system, opioid receptors are located within the wall of the gut– responsible for the powerful constipating effects. Receptors in peripheral tissues such as joints seem to regulate inflammation.
Mechanism of Opioid Dependence
Opioid dependence is a neurobehavioral disorder characterised by a repeated, compulsive seeking or use of opioid medication. The predisposition for developing opiate addiction depends on the complex interaction between genetics, environmental factors, and the pharmacological effects of opiates. Environmental factors like availability of opiates from an early age, perceived risk of opiate use, psychosocial factors, and learned coping strategies all regulate the risk of developing an opiate addiction. Researchers also reveal an association between post-traumatic stress disorder and opiate addiction with an over-representation in the prevalence of this disorder in opiate addicts compared to the control population.
Opioid dependence is accompanied by well-described physical dependence with withdrawal syndrome and tolerance. Opiate addiction includes not only abuse of illicit heroin and other opium derivatives, but also the less commonly recognised problem of misuse and chronic abuse of prescription opioid pain relief medications, such as oxycodone, hydrocodone, codeine, etc.
Drug dependence is referred to a drug-induced clinical state in which, in which drug cessation results in physical and/or psychological withdrawal symptoms. Like many definitions, this is a blurry one.
Underpinnings of the behavioural disease state of opioid dependence
One addiction theory, including that of Robbins, Everitt, Wise, Berridge, Kalivas, Robinson, and Piazza stems from many decades of addiction research. This theory proposes the 3 steps model for the development of opioid dependence:
1st step: development of a reward learning process with drug consumption.
2nd step: escalated drug use in vulnerable individuals with hypo-dopaminergic systems and impaired prefrontal cortex inhibitory control.
3rd step: This step leads to the addiction phenotype, is described as a result of allostatic drug-induced changes in reward circuitry in your neurons which result in a strong desire for drugs (incentive-sensitisation).
This model emphasises positive reinforcement. The driver for addiction seems to be the modified reward circuitry and loss of inhibitory control, with the inference of altered plasticity of synapses in cortical-striatal neuronal circuits and switching from goal-directed to habitual circuitry.
Opioid withdrawal syndrome – What are the symptoms?
Short-acting opioids (e.g. heroin): withdrawal symptoms ensue within 8-24 hours after last use; the phase lasts for 4-10 days.
Long-acting opioids (e.g. methadone): withdrawal symptoms ensue within 12-48 hours after last use; the phase lasts for 10-20 days.
Nausea and vomiting
Hot and cold flushes
Watery discharge from eyes and nose
What is Opioid Maintenance Therapy?
The primary driver of ongoing drug use is the negative reinforcement of withdrawal symptoms. Several strategies to relieve opiate withdrawal symptoms have been evaluated. An integrated global therapeutic approach towards pharmacotherapeutic decisions for opioid dependence should be adopted. This will include psychosocial support, focusing on the individual’s functional recovery. In this respect, Opioid maintenance treatments (OMTs) remains the gold standard medication for opioid dependence. While opioid medications are generally indicated for treating pain, when used as OMTs, they have their specific indication and their particular criteria of use. Methadone, buprenorphine, and naltrexone are each approved for the long-term treatment of opiate addiction.
Buprenorphine has more recently emerged as an efficient treatment for opioid dependence. It has been marketed only since the 1990s for this use. In 2018, it was administered to 220,000 patients in Europe, and it was the most frequently prescribed OMT in the following 8 countries, including France, Sweden, Norway, Finland, and Greece. Prolonged-release depot injection and implantable formulations of buprenorphine are extremely recent novel developments in the treatment of opioid dependence. Such formulations remove the need for daily dosage and offer patients sustained concentrations of buprenorphine over weeks or months.
Let’s explore the 2 case studies authored by our Medical Director Prof. Oscar D’Agnone: “Successful Treatment of Opioid Dependence with Flexible Doses of Injectable Prolonged Release Buprenorphine”, published in Case Reports in Psychiatry recently. 
Case Study 1 Summary:
A 52-year Caucasian male with a history of 22-years of intermittent heroin (injectable) use was started on prolonged release buprenorphine OMT. The patient was shifted from the initial treatment plan of oral buprenorphine to prolonged released buprenorphine due to daily intake challenges and work-life balance. The patient was started on 24 mg Buvidal®, subcutaneous injection after appropriate evaluation. At the 1st-week follow-up visit, the patient was stable, upon which he was administered a further dose of 96 mg buprenorphine for the following month.
Three months of continuous therapy resulted in complete abstinence of all drugs, including alcohol and tobacco – with a complete absence of cravings and improvements in all aspects of his life. His relationships with friends and family improved significantly.
Case Study Summary 2:
A 56-year-old Caucasian female with an extensive 25 years’ history of heroin use, chose prolonged-release buprenorphine treatment as a part of a care plan for OD. The patient relapsed on her initial treatment of oral methadone of 60 ml per day. The patient was selected for prolonged-release buprenorphine and was started on oral buprenorphine one week prior to starting the treatment. During the 4 months of therapy there were no signs on relapse, and the patient appeared stable, happy and content. In fact, according to the patient, it was the first time in her life that had been successful in maintaining abstinence.
Misconceptions Around the Use of OMT:
Since maintenance medications (methadone and buprenorphine) are opioids themselves and are able to produce euphoria in individuals who are not drug-dependent, many people perceive that this form of treatment just substitutes a new substance use disorder instead of an old one. This belief has, unfortunately, stalled the acceptance of these effective treatments. Previously, even some inpatient treatment programmes that were otherwise evidence-based did not allow patients to use these medications, in favour of an "abstinence-only" viewpoint.
Although it is possible for people who don’t have opioid dependence to get high on methadone or buprenorphine, these medications affect people who have developed a high tolerance to opioids in a different way. At the recommended doses, and as a result of their pharmacokinetic and pharmacodynamic properties (the way they attach and affect opioid receptor sites and due to their property of being slowly metabolised in the body), these drugs do not produce a euphoric effect but instead minimise cravings and withdrawal symptoms. This allows the patient to achieve stability and function normally, fulfil school or work responsibilities, and participate in other forms of treatment or support group recovery services to help them become free of their opioid dependence over time.
 Oscar D’Agnone, The OAD Clinic: Successful Treatment of Opioid Dependence with Flexible Doses of Injectable Prolonged Release Buprenorphine, Case Reports in Psychiatry, Volume 2019, Article ID 9381346, 4 pages, https://doi.org/10.1155/2019/9381346