Opioid receptors were first discovered in the early 1970s (Berrocoso, Sánchez-Blázquez, Garzón, & Mico, 2009). Their discovery led to the identification of various endogenous opioid peptides (e.g., dynorphins, enkephalins, endorphins), which are naturally produced in the brain. The effects of endogenous opioid peptides and exogenous opioid drugs (e.g., heroin, morphine) are mediated by three major opioid receptor subtypes, referred to as mu-opioid (MOP), delta-opioid (DOP), and kappa-opioid (KOP), although other receptor subtypes have been characterized.
Opioid receptors are widely distributed throughout the central and peripheral nervous system, and they are co-localized on neurons or within neuronal pathways served by other neurotransmitters (i.e., norepinephrine, serotonin, dopamine, acetylcholine, and glutamate). This suggests that, in addition to their central role in brain pathways mediating pain, endogenous opioid peptides function as neuromodulators, whereby they interact with and modulate the activity of other neurotransmitter systems. As such, opioid systems appear to be involved in many physiological functions in the nervous system. In this article, I describe some of the diverse clinical uses of opioid receptor drugs.
Methadone (Dolophine®), a synthetic opioid analgesic drug, is an agonist at the MOP receptor. This agonist effect mimics the actions of enkephalins and endorphins. Stimulation of MOP receptors inhibits or alters the rate of release of other neurotransmitters such as acetylcholine, norepinephrine, and dopamine. As a result, methadone does not produce the same type of euphoria or “high” seen with other opioid drugs. Methadone is approved by the U.S. Food and Drug Administration (FDA) for analgesia, detoxification from opioid drug addictions, and as a maintenance treatment for opioid dependence. Possible adverse effects are sedation, lightheadedness, dizziness, nausea, vomiting, constipation, sweating, sexual dysfunction, and weight gain. Rare serious side effects include respiratory depression, hypotension, and cardiac arrhythmias. Tolerance, dependence, and abuse are possible.
Buprenorphine (Buprenex®, Subutex®), a synthetic opioid analgesic drug, is a partial MOP receptor agonist and KOP receptor antagonist. This mixed agonist/antagonist effect may produce less euphoria, with a lower liability for tolerance, dependence, and abuse compared with other opioid drugs. Buprenorphine has FDA-approved indications for analgesia, detoxification from opioid drug addictions, and as a treatment for opioid dependence. Compared with methadone, it does not have significant adverse cognitive effects. Possible adverse effects are sedation, lightheadedness, dizziness, nausea, vomiting, constipation, and sexual dysfunction. Compared with methadone, it is less likely to cause respiratory depression, hypotension, or cardiac arrhythmias. Tolerance, dependence, and abuse are possible.
A considerable amount of preclinical animal research and, to a lesser extent, human research has demonstrated that functional abnormalities in opioid systems may be involved in the pathophysiology of depression. Opioid receptors are found in brain regions that are involved in mood regulation, and these receptors have a reciprocal and interactive modulating effect on the function of various neurotransmitter systems. As a result, modulation of opioid systems is a novel treatment approach for depression, and opioid drugs were often used to treat depression until the mid-1950s (Gold, Pottash, Sweeney, Martin, & Extein, 1982). Many non-opioid antidepressant drugs directly and indirectly affect opioid receptors. Improvement in mood has been observed in patients during treatment with cyclazocine, which is a mixed agonist/antagonist opioid drug not currently available (Fink, Simeon, Itil, & Freedman, 1970), as well as during beta-endorphin infusions and with the use of a synthetic enkephalin analogue (Gold et al., 1982).
In an open-label study involving 40 opioid addicts treated as outpatients with buprenorphine for a month, depressive symptoms significantly decreased in the 19 patients who were depressed at intake (Kosten, Morgan, & Kosten, 1990). Rapid improvement in mood was observed in 7 of 10 non-opioid abusing patients with refractory depression (Bodkin, Zornberg, Lukas, & Cole, 1995). A double-blind, placebo-controlled crossover study of buprenorphine demonstrated a significant improvement in depression in 4 patients and a slight to moderate response in the remaining 9 patients (Emrich, Vogt, & Herz, 1982).
Naltrexone (Revia®) is a pure opioid receptor antagonist drug (i.e., it has no agonist effects on any opioid receptor subtype). It can be used for rapid detoxification from opioid drug addictions. Naltrexone has FDA-approved indications for the treatment of opioid and alcohol dependence. Its use for alcohol dependence is based on animal studies suggesting that endogenous opioid systems may modulate the intake of alcohol. Subsequent human clinical trials demonstrated the ability of naltrexone to decrease alcohol craving and decrease drinking of alcoholic beverages. A form of naltrexone (Vivitrol®) can be given as a monthly intramuscular injection for the maintenance of abstinence in alcohol dependence. Possible adverse effects are anxiety, headache, nausea, constipation, and abdominal pain. Liver damage is a rare serious adverse effect. Naltrexone can interfere with the analgesic effects of narcotic drugs and can precipitate withdrawal symptoms in opioid-dependent patients.
Naltrexone has been shown to be modestly effective in treating self-injurious behaviors in various patient populations with autism and mental retardation, according to a number of small- to medium-sized randomized, double-blind, placebo-controlled crossover studies (Anderson et al., 1997; Bodfish et al., 1997). The putative mechanism of action of this effect is partly based on opioid receptor antagonism in brain regions that are important for rewarding and reinforcing behaviors, an effect which would attenuate the self-reinforcement of maladaptive behaviors. Modulation of serotonin function might also play a role in mediating this clinical effect.
On the basis of a similar putative neurobiological mechanism of self-reinforcement of maladaptive behaviors, naltrexone has been investigated in bulimia nervosa (characterized by binging and purging behaviors). High-dosage naltrexone (200 mg per day) was reported to be effective in the treatment of bulimia nervosa in an uncontrolled study involving 5 women (Jonas & Gold, 1986). However, two double-blind, placebo-controlled trials using lower dosages (50 mg per day) did not confirm the efficacy of naltrexone in bulimia nervosa (Huseman, Pearson, Madison, & Leuschen, 1990; Mitchell et al., 1989).
Dopamine receptor-blocking drugs (e.g., antipsychotic agents) are typically used to control vocal and motor tics. Because opioid receptors can modulate dopamine transmission, naltrexone has been studied in Tourette syndrome. In a randomized, double-blind, controlled trial comparing naltrexone, propoxyphene (Darvon®), and placebo in 10 adults, naltrexone was significantly superior in efficacy (Kurlan et al., 1991). Propoxyphene is an opioid analgesic drug that is structurally similar to the MOP agonist methadone.
Naltrexone was found to be effective in alleviating symptoms of premenstrual syndrome in a double-blind, placebo-controlled study involving 20 women (Chuong, Coulam, Bergstralh, O’Fallon, & Steinmetz, 1988). Since serotonergic anti-depressant agents are effective for the treatment of premenstrual symptoms, naltrexone’s effect may be related to modulation of serotonin activity.
Naloxone (Narcan®) is an opioid receptor antagonist drug, with greatest binding to the MOP receptor subtype but also binding to KOP and sigma receptor subtypes. It is most commonly used to treat opioid drug intoxication or overdoses in emergencies (e.g., rapidly reversing respiratory depression, comas following overdoses with heroin and other opioid drugs). Giving naloxone to an opioid-dependent person will immediately precipitate signs and symptoms of withdrawal (i.e., anxiety, runny nose, dilated pupils, elevated heart rate, increased blood pressure, sweating, nausea, abdominal pain, and diarrhea). This effect has been used to diagnose opioid dependence.
Similar to the putative dopamine-modulating effects of naltrexone, naloxone has been investigated in several different patient populations where dopamine-blocking drugs are used clinically. In a small randomized, double-blind, placebo-controlled study of 5 patients with Tourette syndrome, four different dosages of naloxone were evaluated (Chappell et al., 1992). Naloxone was not associated with any dramatic effects on motor or vocal tics, but there was an increase in motor tics in response to the two low dosages of naloxone. A double-blind, placebo-controlled trial did not demonstrate any efficacy in the acute treatment of manic symptoms (Davis et al., 1980). Two double-blind placebo-controlled studies found that naloxone was not effective in patients with schizophrenia (Naber et al., 1983; Pickar et al., 1989).
Naloxone produced improvement in involuntary movements, cognition (memory and problem solving), and clinical ratings in patients with tardive dyskinesia in a placebo-controlled study (Lindenmayer et al., 1988). A second double-blind, placebo-controlled study investigated naloxone in 13 patients with tardive dyskinesia (Blum, Nisipeanu, & Roberts, 1987). Three patients showed significant improvement, although it is notable that these 3 patients had had tardive dyskinesia for a relatively short duration (less than 3 years) compared with the other patients, who had tardive dyskinesia for up to 20 years.
Buprenorphine/naloxone (Suboxone®) is a combination product that is FDA approved for the maintenance treatment of opioid dependence. Possible adverse effects are headache, nausea, vomiting, constipation, abdominal pain, and sweating. Respiratory depression and hypotension are possible but rare.
Various opioid receptor drugs have been investigated for the treatment of addictions and other mental disorders. Although some of these investigations are relatively dated, their findings are still relevant today. Nurses should be familiar with the clinical use of these types of drugs, as well as the rationale for their use, as further development is especially likely to occur in the treatment of addictions and mood disorders.
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