Compounded Low Dose Naltrexone (LDN) Capsules

Naltrexone is an oral opiate receptor antagonist. It is derived from thebaine and is very similar in structure to oxymorphone. Like parenteral naloxone, naltrexone is a pure antagonist (i.e., agonist actions are not apparent), but naltrexone has better oral bioavailability and a much longer duration of action than naloxone. Clinically, naltrexone is used to help maintain an opiate-free state in patients who are known opiate abusers. Naltrexone is of greatest benefit in patients who take the drug as part of a comprehensive occupational rehabilitative program or other compliance-enhancing program. Unlike methadone or LAAM, naltrexone does not reinforce medication compliance and will not prevent withdrawal. Naltrexone has been used as part of rapid and ultrarapid detoxification techniques. These techniques are designed to precipitate withdrawal by administering opiate antagonists. These approaches are thought to minimize the risk of relapse and allow quick initiation of naltrexone maintenance and psychosocial supports. Ultrarapid detoxification is performed under general anesthesia or heavy sedation. While numerous studies have been performed examining the role of these detoxification techniques, a standardized procedure including appropriate medications and dose, safety, and effectiveness have not been determined in relation to standard detoxification techniques.^[1] Naltrexone supports abstinence, prevents relapse, and decreases alcohol consumption in patients treated for alcoholism. Naltrexone is not beneficial in all alcoholic patients and may only provide a small improvement in outcome when added to conventional therapy. The FDA approved naltrexone in 1984 for the adjuvant treatment of patients dependent on opiate agonists. FDA approval of naltrexone for the treatment of alcoholism was granted January 1995. The FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation used to help control cravings for alcohol in April 2006, and then in October 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence after opioid detoxification.

Like naloxone, naltrexone is a competitive antagonist at opiate receptors mu, kappa, and delta. Opiate receptors have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Naltrexone can either displace opiate agonists from binding at these receptors or prevent opiate binding. Naltrexone does not antagonize the effects of non-opiates such as cocaine, ethanol, amphetamines, barbiturates, or benzodiazepines. Blockade of opiate receptors by naltrexone is a competitive phenomenon and results in elimination of the euphoric effect of opiates. At usual opiate concentrations, naltrexone’s greater affinity for the receptor prevents the binding of the opiate agonist to the receptor. However, when opiate concentrations are extremely high, the opiate can displace naltrexone, and respiratory depression and/or death is possible. Although naltrexone itself may possess some agonistic properties, these are minor compared to its potent antagonistic actions. Naltrexone is 17-times more potent than nalmorphine and twice as potent as naloxone. In patients who are physically dependent on opiates, naltrexone will precipitate an opiate withdrawal syndrome. Naltrexone use is not associated with tolerance or dependence, therefore, withdrawal from naltrexone does not occur. When co-administered with opiate agonists, naltrexone blocks the physical dependence to morphine, heroin, and other opiate agonists. Depending on the dose, the clinical effects of naltrexone can persist for up to 72 hours.

Endogenous opiods such as beta-endorphins and enkephalins may play an important role in alcoholism. An opioid reward system mediated by mu- and delta-receptors and an opposing aversions system mediated by kappa-receptors must be in balance to maintain a neutral state in regards to the development of addiction. Several therories regarding alcohol addiction and the function of endongeous opioids exist. All of these therories are based on an imbalance in favor of the endongenous reward pathways due to alcohol. Naltrexone inhibits the effects of endogenous opioids and decreases the positive or reward pathways associated with alcoholism. Naltrexone is not aversive therapy and will not produce a disulfiram-like reaction if opiates or ethanol are ingested while receiving naltrexone.

Naltrexone is contraindicated in patients with hypersensitivity to naltrexone or any components of the commercially available product. Naltrexone is incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres. The diluent is composed of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection. Naltrexone should also not be used in patients with a known hypersensitivity to naloxone or nalmefene because these three drugs are all structurally similar.

The use of naltrexone in patients with hepatic disease should be carefully considered due to the hepatotoxic effects of naltrexone and the potential for decreased clearance of naltrexone. Naltrexone does not appear to be hepatotoxic at recommended doses. However, the margin between a safe dose and a hepatotoxic dose appears to be five-fold or less. There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits. There are reports of hepatitis and significant hepatic dysfunction in association with exposure to naltrexone oral tablets and parenteral naltrexone. In patients treated with naltrexone tablets or injection who presented with elevated transaminases, other potential causes were often identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Opioid withdrawal does not typically manifest as clinically significant hepatic dysfunction, however, abruptly precipitated opioid withdrawal may lead to systemic sequelae including acute liver injury. Warn patients of the potential risk of hepatic injury and advise them to seek medical attention if they experience symptoms of acute hepatitis. Discontinue use of naltrexone if signs/symptoms of acute hepatitis occur.^[2]^[3]^[4]

Depression, suicide, attempted suicide and suicidal ideation have been reported in patients receiving naltrexone for the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions. Monitor alcohol and opioid dependent patients, including those taking naltrexone, for the development of depression or suicidal thinking. Inform families and caregivers of patients being treated with naltrexone to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.^[4]

Naltrexone is contraindicated in patients who are receiving opioid analgesics, partial opiate agonists (e.g., buprenorphine), those with current physiologic opioid dependence, and those in acute opioid withdrawal. Administration of naltrexone to these patients may precipitate an abrupt withdrawal severe enough to require hospitalization, and in some cases management in the intensive care unit. To prevent precipitation of withdrawal, patients should be opioid-free (including tramadol) for a minimum of 7—10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. In every case, be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. Since the absence of an opiate drug in the urine is often not sufficient proof that a patient is opiate-free, a naloxone challenge should be done if there is any question of occult opioid dependence. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. A positive reaction to the naloxone challenge predicts a similar response to naltrexone. Use of naltrexone is contraindicated in an individual who fails the naloxone challenge test or who has a positive urine test for opioids.The naloxone challenge can be repeated in 24 hours. Assess patients treated for alcohol dependence for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.^[2]^[3]^[4]

If a painful procedure such as surgery is planned, then naltrexone should be discontinued 72 hours prior to the procedure. Patients should be abstinent from opiate analgesia for at least 7 days before restarting naltrexone.

Naltrexone treated patients who require emergent opiate analgesia may require the administration of large opiate doses to provide adequate pain control, which may increase the risk of deep or prolonged respiratory depression. A rapidly acting opiate agonist is preferred for emergent analgesia to limit the duration of respiratory depression. Non-opiate receptor mediated actions (i.e., histamine-mediated) may occur with the use of opiates and should be expected (e.g., facial swelling, itching, generalized erythema or bronchoconstriction). Other alternatives for emergent analgesia in patients taking naltrexone include the use of regional analgesia, conscious sedation, non-opiate analgesics, or general anesthetics.

Attempts to overcome the antagonistic effects of naltrexone with large doses of an opiate agonist by patients maintained on naltrexone may result in potential for overdose or poisoning that may be fatal; cases of opioid overdose with fatal outcomes have been reported in patients after discontinuing treatment. Despite a prolonged pharmacologic effect, the blockade produced by naltrexone is surmountable. As the naltrexone blockade wanes and eventually dissipates, patients may respond to lower doses of opioids than previously used, potentially resulting in life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Patients are at particular risk at the end of the dosing interval, after missing a scheduled dose or after discontinuing naltrexone treatment. Patients should be informed of the serious consequences of attempting to overcome the opiate blockade and that they may be more sensitive to lower doses of opiate agonists once naltrexone therapy is stopped. Advise patients to inform family members and those closest to them of this increased sensitivity and risk of overdose.^[2]^[3]^[4]

Naltrexone and its major active metabolite are excreted primarily by the kidney. Use caution in administering naltrexone to patients with renal impairment. Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with a creatinine clearance of 50—80 ml/minute. The disposition of naltrexone in patients with moderate to severe renal impairment has not been evaluated. Dosage adjustments may be necessary in patients with renal dysfunction.

Naltrexone is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. In some individuals, opiate antagonists have been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones, although the clinical significance is not known. In rat studies, there was an increase in early fetal loss and pseudopregnancy, and a decrease in pregnancy rate. There was no evidence of teratogenicity; however, rats do not form a significant amount of the major human metabolite, 6-B-naltrexol; therefore, the potential reproductive toxicity of 6-B-naltrexol in rats is not known. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice.^[2] When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown.

According to the manufacturer, naltrexone and its metabolite are excreted into human milk, and a decision should be made to discontinue breast-feeding or discontinue naltrexone, taking into consideration the importance of the drug to the mother. Animal studies have shown the potential for tumorigenicity.^[2] No reports describing the use of naltrexone during breast-feeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant.^[5] If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse deterrent during breast-feeding.

The safe use of naltrexone in neonates, infants, children, and adolescents < 18 years has not been established. Naltrexone may cause dizziness (see Adverse Reactions). Tell patients about the importance of not driving or operating machinery until they know how this medicine will affect them. Administer the extended-release injectable suspension of naltrexone cautiously to patients with thrombocytopenia, coagulopathy, or other bleeding disorders. Patients with thrombocytopenia, vitamin K deficiency, a coagulopathy (e.g., hemophilia), or receiving anticoagulant therapy should be monitored closely when given intramuscular naltrexone because bleeding can occur at the IM injection site. All steps to avoid hematoma formation are recommended. Naltrexone extended-release injectable suspension (Vivitrol) is only for intramuscular administration; intravenous administration and subcutaneous administration should be avoided. The risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue (see Adverse Reactions). Proper administration techniques and patient selection are imperative (see Administration). Consider alternate treatment for patients whose body habitus (obesity) precludes a gluteal intramuscular injection with the provided needle. Women may be physiologically at higher risk for injection site reactions because of typically higher gluteal fat thickness, and in fact, post-marketing reports of injection site reactions occur primarily in females. Also, a variable depth of subcutaneous tissue exists between patients; the depth is dependent on the gender and weight of the patient.

Naltrexone is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. In some individuals, opiate antagonists have been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones, although the clinical significance is not known. In rat studies, there was an increase in early fetal loss and pseudopregnancy, and a decrease in pregnancy rate. There was no evidence of teratogenicity; however, rats do not form a significant amount of the major human metabolite, 6-B-naltrexol; therefore, the potential reproductive toxicity of 6-B-naltrexol in rats is not known. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice.^[2] When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown.

According to the manufacturer, naltrexone and its metabolite are excreted into human milk, and a decision should be made to discontinue breastfeeding or discontinue naltrexone, taking into consideration the importance of the drug to the mother. Animal studies have shown the potential for tumorigenicity.^[2] No reports describing the use of naltrexone during breast-feeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant.^[5] If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse deterrent during breastfeeding.