Drugs Currently on the Market for the Treatment of Addiction – Preclinical Background


• Methadone (Dolophine). Methadone is a μ opioid receptor agonist with a long oral half-life in humans (22–30 h; racemic mixture used in the clinic). It has been an effective substitution pharmacotherapy used for over 40 years in the treatment of opioid addiction (Box 9.4). Methadone has a much shorter half-life in animals than in humans. Chronic 5 day treatment in nondependent rhesus monkeys had little effect on heroin choice but prevented withdrawal-associated increases in heroin choice. Using a slow-release subcutaneous minipump to mimic the pharmacokinetic profile of humans, methadone also blocked cocaine seeking in rats in the conditioned place preference paradigm, blocked responding on a progressive-ratio schedule of reinforcement, and blocked reinstatement at doses that did not have effects on locomotor activity, food intake, or pain responsivity. Human laboratory studies support the clinical observation that persistent heroin use may be reduced by providing larger methadone maintenance doses, because such doses completely block the subjective effects of heroin and produce greater withdrawal suppression during outpatient periods. • Buprenorphine (Subutex, Suboxone). Buprenorphine is an effective maintenance pharmacotherapy for the treatment of opioid addiction. It is a μ opioid partial agonist, a full δ and κ antagonist, and nociceptin receptor partial agonist (for further reading, see Cowan, 2007). It has pharmacological properties that provide a good safety profile, low physical dependence, and flexibility in dose scheduling. The finding that buprenorphine dose-dependently decreased heroin intake in heroin-dependent animals is consistent with predictive validity for the self-administration dependence model. Buprenorphine was effective in reducing the self-administration of other drugs of abuse in rats, even when the μ opioid receptor was concurrently blocked, suggesting that κ antagonist and nociceptin agonist activity may be effective in modulating the negative reinforcement associated with dependence. Buprenorphine decreases intravenous heroin self-administration in human laboratory studies. From the perspective of the abuse potential of buprenorphine itself, it has reinforcing, discriminative stimulus, and physical dependence-producing effects, but it has less abuse liability than morphine. Buprenorphine maintains lower breakpoints than full agonists in progressive-ratio self-administration procedures. Withdrawal from buprenorphine is characterized by a mild morphine-like abstinence syndrome in animals and humans. Buprenorphine may suppress or precipitate withdrawal in animals maintained on chronic administration of a μ agonist. Lower doses suppress spontaneous withdrawal signs, and higher doses can precipitate an abstinence syndrome.

BOX 9.4


Substitution or replacement pharmacotherapy is a medical procedure used with opioid drugs to replace a drug of addiction with a longer-acting but less euphoria-inducing opioid, such as methadone or buprenorphine. The main principle behind opioid substitution is that an individual with opioid addiction will be able to regain a normal life and schedule while being treated with a substance that stops the person from experiencing withdrawal symptoms and drug cravings, but the replacement substance does not produce strong euphoria. The individual theoretically shows no compulsive drug seeking, because both withdrawal and craving are blocked by full opioid receptor occupancy of the substitution drug. From the public health perspective, reductions of intravenous opioid use bring significant health benefits, such as a lower incidence of HIV/AIDS and hepatitis C infections, and a lower incidence of all other associated complications, such as legal and psychosocial problems, that result from intravenous drug use. However, there is no reversal of neuroadaptations in the brain, and the individual remains dependent and will manifest withdrawal and severe craving if the substitution drug is abruptly removed.
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