1) Lozenges: 200 mcg, 300 mcg, or 400 mcg
2) Injection: 0.05 mg/mL or 50 mcg/mL
3) Transdermal patches: 2.5 mg, 5 mg, 7.5 mg or 10 mg
4) Oral transmucosal

a) CASE REPORT: Withdrawal seizures were reported in a newborn infant exposed in utero to fentanyl (150 mcg/hr) for 8 days during the 31st week of gestation (Anwar et al, 1995).

a) CASE REPORT: A 21-year-old man, who had been abusing oxycodone, oxymorphone, cannabis, and heroin, developed severe opioid withdrawal symptoms that began a day after using buprenorphine-naloxone illegally for self-detoxification. On day 2, he took three 45-minute hot showers after developing diaphoresis, chills, and nausea. The next day, he developed gooseflesh and diarrhea and again took three more 45-minute hot showers. He developed severe muscle cramps that night and persistent vomiting over the next 24 hours. He presented to the ED the next day with swollen throat and dyspnea. His vital signs included a temperature of 96.4 degrees F, blood pressure of 136/77, pulse of 202 beats/min, and respiratory rate of 24 breaths/min. He had severe anxiety requiring treatment with lorazepam. An ECG result was normal, but a CT scan of his chest and neck revealed pneumomediastinum. He received piperacillin-tazobactam after he was diagnosed with esophageal tear. At this time, a thoracic surgery was considered, but he became disoriented. Laboratory analysis showed acute renal failure (serum creatinine of 5.05 mg/dL; BUN of 29 mg/dL). He received vancomycin and piperacillin-tazobactam to treat pneumomediastinum which was possibly secondary to esophageal perforation and acute opioid withdrawal. After his transfer to the ICU, he began feeling flushed and hot, fidgety, and very confused with incoherent speech. Despite treatment with lorazepam, his condition did not improve. He received haloperidol, which made him drowsy, but continued to have agitation, jerking, and confusion. He also reported auditory, visual, and tactile hallucinations during the first night of hospitalization. Although his delirium could be from opioid withdrawal, it might have been caused by a paradoxical reaction to lorazepam, which was worsened by haloperidol causing a superimposed akathisia. Lorazepam and haloperidol were discontinued and buprenorphine-naloxone combination was restarted. He developed 2 episodes of dystonia which were treated with diphenhydramine. Laboratory results revealed normal serum creatinine level and negative blood and urine cultures, but his CK continued to increase to 29,661 Units/L. Following further supportive care, including 2 doses of buprenorphine-naloxone, his withdrawal symptoms gradually improved and he was discharged on day 8 (Gangahar, 2015).

1) NALORPHINE (Briggs et al, 1998)

1) ALFENTANIL HYDROCHLORIDE* (Prod Info ALFENTA(R) IV injection, 2008)
2) ALPHAPRODINE* (Briggs et al, 1998)
3) BUTORPHANOL (Prod Info butorphanol tartrate nasal spray, 2009)
4) CODEINE SULFATE (Prod Info Codeine sulfate oral tablets, 2009)
5) ETHOHEPTAZINE* (Briggs et al, 1998)
6) FENTANYL (Prod Info ACTIQ(R) oral transumcosal lozenge, 2009)
7) HYDROCODONE* (Briggs et al, 1998)
8) HYDROMORPHONE (Prod Info EXALGO(R) extended release oral tablets, 2010)
9) LEVORPHANOL (Prod Info Levorphanol tartrate oral tablets, 2008)
10) MEPERIDINE (Prod Info DEMEROL(R) oral solution, oral tablets, 2008)
11) METHADONE (Prod Info methadone hydrochloride oral solution, 2008)
12) MORPHINE (Prod Info MS CONTIN(R) controlled-release oral tablets, 2009)
13) OPIUM (Prod Info opium tincture (DEODORIZED) oral solution, 2008)
14) OXYMORPHONE (Prod Info OPANA(R) ER extended-release oral tablets, 2010)
15) PAREGORIC SYRUP (Prod Info paregoric oral solution, 1996)
16) PHENAZOCINE* (Briggs et al, 1998)

a) *Risk Factor D if used for prolonged periods or in high doses at term (Briggs et al, 1998).

1) ANILERIDINE* (Briggs et al, 1998)
2) DIHYDROCODEINE BITARTRATE* (Briggs et al, 1998)
3) HEROIN* (Briggs et al, 1998)
4) NALBUPHINE (Prod Info nalbuphine hydrochloride subcutaneous injection, IM injection, IV injection, solution, 2007)
5) OXYCODONE (Prod Info oxycodone hydrochloride oral capsules, 2010)

a) *Risk Factor D if used for prolonged periods or in high doses at term (Briggs et al, 1998).

a) METHADONE serum levels may be useful for regulation of patients on a methadone maintenance schedule, although they are rarely used in clinical practice. Trough plasma concentrations of 150 to 200 ng/mL have been reported to be optimal for maintaining appropriate opioid levels with minimal symptoms of withdrawal (Dyer et al, 1999; Borg et al, 1995).
b) Torrens et al (1998) reported no correlation between opioid withdrawal scale scores and plasma methadone concentrations in former heroin addicts on a methadone maintenance treatment program. They suggest therapeutic drug monitoring during methadone maintenance may be useful for compliance with therapy, but not for predicting heroin use and subjective withdrawal symptoms.

a) Pharmacologic therapy of neonatal withdrawal may include tincture of opium or paregoric and sedative-hypnotic agents. Opioid agonists may be more effective for prevention of withdrawal (from heroin or methadone) than phenobarbital or diazepam. In the case of maternal abuse of both opioids and sedative-hypnotics, phenobarbital may have a role in therapy, although oral dosing may lead to a delay in achieving therapeutic levels. Phenobarbital and diazepam have been found to significantly suppress normal sucking behavior, while opioids do not (Franck & Vilardi, 1995).
b) SEIZURES/HYPERACTIVITY: PAREGORIC or a 1:25 dilution of opium tincture (0.4 mg/mL diluted) in a dosage of 0.2 mL orally for either drug every 3 hours (or 0.3 mg/kg/day administered in 6 divided doses), increased by 0.05 mL at each dose until withdrawal symptoms are controlled, up to a maximum of 0.7 mL per dose for a full-term infant (or 0.8 mg/kg/day). Following stabilization, continue therapy for 3 to 5 days and taper gradually over a 2- to 4-week period (up to 40 days) (or taper by 10% to 20% each day and stop when dosage is 0.2 mg/kg/day). Reserve parenteral morphine for short-term therapy only in severe cases, because it contains sodium bisulfite and phenol (Hamilton, 1998) (Anon, 1983). Paregoric also preserves the suck reflex while preventing seizure activity, unlike diazepam. These drugs can cause respiratory depression, which should be monitored (Lifshitz et al, 2001; Fine, 1998).
c) SEIZURES/HYPERACTIVITY: DIAZEPAM may be used for neonatal narcotic withdrawal and has been given in doses of 1 to 2 mg every 8 hours. Due to limited capacity to metabolize and excrete this drug in the neonate, it may take 1 month or longer for total elimination. Parenteral diazepam, containing benzyl alcohol, is contraindicated in a jaundiced infant or a premature infant (Anon, 1983).
d) SEIZURES/HYPERACTIVITY: PHENOBARBITAL may be used to treat hyperactive behavior in the infant manifesting narcotic withdrawal; phenobarbital does not relieve gastrointestinal (GI) symptoms. Large doses may significantly suppress the CNS, impair the suck reflex, and delay bonding between mother and infant. Therapeutic serum levels necessary for control of withdrawal symptoms are not established. Neonatal loading dose of 20 mg/kg has been used. Obtain a serum level 24 to 28 hours later and adjust maintenance dose according to symptomatology and phenobarbital concentration. Maintenance doses of 2 to 8 mg/kg/day or 3.5 to 5 mg/kg every 8 to 12 hours have been given. Following stabilization, decrease dose to allow drug level to decrease by 10% to 20% per day (Lifshitz et al, 2001; Anand & Arnold, 1994) (Anon, 1983). Phenobarbital may be given alone or in combination with paregoric or diazepam. Phenobarbital is NOT recommended as a primary agent in the management of neonatal withdrawal, due to its prolonged half-life, induction of hepatic microsomal enzymes, and rapid tolerance to its sedative properties.
e) HYPERACTIVITY: CHLORPROMAZINE may reduce irritability, tremors, and GI symptoms in neonates. Recommended dose is 0.3 to 0.75 mg/kg every 6 to 8 hours, depending on the severity of withdrawal. The routine use of chlorpromazine is NOT recommended due to adverse effects, particularly neurological (Suresh & Anand, 1998; Anand & Arnold, 1994).
f) HYPERACTIVITY: CLONIDINE, which mimics the opioids at the superselector levels, has been studied in neonatal withdrawal. Oral doses of 3 to 4 mcg/kg have been shown to decrease the severity of neonatal withdrawal symptoms over a period of 2 to 3 weeks. Adverse effects include sedation, bradycardia, and hypotension. This method cannot yet be recommended until further studies have been published (Suresh & Anand, 1998; Anand & Arnold, 1994).

a) Seizures and hallucinations are almost always associated with concomitant withdrawal from sedative/hypnotics, except in neonates where seizures are noted.
b) Patients addicted may wish maintenance therapy, which is accomplished in some centers through the use of methadone or long-acting opioid agonists.
c) Naloxone should be used with caution in patients that may be opioid abusers. Its use may precipitate opioid withdrawal (Popper et al, 1989). Once the patient is opioid free for 1 week, naltrexone (opioid antagonist) may be started for prevention of relapse.
d) Management of withdrawal in the confirmed addict may be accomplished with the administration of clonidine, by the substitution of methadone or a long-acting agonist, or with the reintroduction of the original addicting agent if available through a recognized drug withdrawal program.
e) REFERENCES: There are many references comparing various medical opioid withdrawal techniques in the literature. The basic therapeutic techniques are described below. Further references include: (O'Connor & Fiellin, 2000; Johnson & McCagh, 2000; Petitjean et al, 2001; Bickel et al, 1999; Mendelson et al, 1999; Umbricht et al, 1999; Eissenberg et al, 1997; Rosen et al, 1996; Strain et al, 1996; Banys et al, 1994; Amass et al, 1994; Fishbain et al, 1993; Kosten et al, 1990; Fudala et al, 1990; Ternes & O'Brien, 1990; Guthrie, 1990)

a) Clonidine is a non-opioid, alpha-adrenergic agonist. Clonidine is most effective in suppressing autonomic signs and symptoms of opioid withdrawal, but is less effective for subjective symptoms. In well-controlled settings with compliant (but selected, not randomized) patients, clonidine 6 mcg/kg acutely and 10 to 17 mcg/kg/day chronically (maximum dose, 25 mcg/kg/day) (for 10 days), has been effective in preventing opioid withdrawal syndrome. Hypotension may rarely occur at higher doses (O'Connor & Fiellin, 2000; Olmedo & Hoffman, 2000; Riordan & Kleber, 1980; Gold et al, 1980; Gold et al, 1978a; Gold et al, 1978b; Gold et al, 1979).
b) Clonidine has been used in opioid detoxification in a primary care setting. Patients have received 0.1 to 0.2 mg of oral clonidine every 4 hours as needed, for up to 7 days, for control of the withdrawal syndrome (O'Connor et al, 1997). Naltrexone may be prescribed following detoxification with clonidine for prevention of relapse. A method of rapid outpatient opioid detoxification has also included the simultaneous use of clonidine and naltrexone, which has been successful over a day period. Sedation and hypotension may occur following clonidine dosing (Stine & Kosten, 1992).
c) A randomized, controlled trial of 106 treatment-seeking heroin-dependent patients (aged 21 through 50 years), comparing 3 different treatment interventions (anesthesia-assisted vs buprenorphine-or clonidine-assisted heroin detoxification and naltrexone induction), did not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction. All 3 treatment interventions had comparable mean withdrawal severities. Although all 3 groups had similar rates of completion of inpatient detoxification, the anesthesia- and buprenorphine-assisted detoxification interventions had significantly greater rates of naltrexone induction (94% anesthesia, 97% buprenorphine) compared with clonidine-assisted detoxification (21%). Over the course of the study (12 weeks), treatment retention did not differ significantly across intervention groups (7 of 35 (29%) in the anesthesia-assisted group, 9 of 37 (24%) in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted group). The risk of dropping out was reduced significantly by induction with 50 mg of naltrexone (odds ratio, 0.28; 95% confidence interval, 0.15 to 0.51). Three potentially life-threatening adverse events were observed in the anesthesia-assisted group (Collins et al, 2005).
d) INTENTIONAL INTRATHECAL OPIOID DETOXIFICATION: Three patients, with intrathecal drug delivery systems (IDDS), inadequate pain control, and declining functionality, developed diuresis, agitation, hypertension, tachycardia, hyperalgesia, mild diarrhea, yawning, and test and smell aversion after the controlled abrupt discontinuation of the intrathecal opioids, without using an opioid bridge. Clonidine was used to treat hypertension and tachycardia. Piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis were not observed in any patients. Upon follow-up, two of the three patients had only slight improvement in pain but all reported improved functional capacity and quality of life (Jackson et al, 2013).

a) Guanfacine has proven to be partially effective in the treatment of withdrawal symptoms of both heroin-addicted patients and patients on methadone maintenance. Comparative studies have shown a similar efficacy for both guanfacine and clonidine. Doses of 3 to 4 mg per day (in 3 divided doses) have been given for about 3 days, then tapered over the next several days (up to 10 days total) (San et al, 1994).

a) Buprenorphine, a partial opioid agonist, precipitates mild withdrawal, while simultaneously minimizing these symptoms by its agonist activity (Stine & Kosten, 1992). Buprenorphine has been given for opioid detoxification (including heroin) in a primary care setting in doses of 3 mg/day sublingually for 3 days, with subsequent clonidine doses on the fourth day (O'Connor et al, 1997). Alternatively, a daily sublingual dose of up to 8 mg/day has been shown to maintain individuals without producing withdrawal symptoms, with a gradual taper over 10 to 36 days (O'Connor & Fiellin, 2000; Vignau, 1998; Eissenberg et al, 1997; Johnson & Fudala, 1992). Less severe withdrawal symptoms have been reported with buprenorphine therapy compared with clonidine therapy. Buprenorphine has been given concurrently with naltrexone in order to shorten opioid detoxification (Umbricht et al, 1999).
b) A randomized, controlled trial of 106 treatment-seeking heroin-dependent patients (aged 21 through 50 years), comparing 3 different treatment interventions (anesthesia-assisted vs buprenorphine-or clonidine-assisted heroin detoxification and naltrexone induction), did not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction. All 3 treatment interventions had comparable mean withdrawal severities. Although all 3 groups had similar rates of completion of inpatient detoxification, the anesthesia- and buprenorphine-assisted detoxification interventions had significantly greater rates of naltrexone induction (94% anesthesia, 97% buprenorphine) compared with clonidine-assisted detoxification (21%). Over the course of the study (12 weeks), treatment retention did not differ significantly across intervention groups (7 of 35 (29%) in the anesthesia-assisted group, 9 of 37 (24%) in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted group). The risk of dropping out was reduced significantly by induction with 50 mg of naltrexone (odds ratio, 0.28; 95% confidence interval, 0.15 to 0.51). Three potentially life-threatening adverse events were observed in the anesthesia-assisted group (Collins et al, 2005).
c) In an outpatient setting, combination therapy with sublingual buprenorphine and naloxone, which is currently under new drug application review with the FDA, has been shown to be as effective as methadone but safer in overdose due to its ceiling effect on respiratory depression. Abuse potential is less; fewer withdrawal symptoms occur when discontinued. The sublingual tablets are available in a 4:1 mg ratio of buprenorphine to naloxone. Two tablet strengths available include 2 mighty mg and 8 Mg++ mg. A combination of both strengths may be given to achieve dosages of 10, 12, 14, 18, 20 or 22 mg (Raisch et al, 2002).
d) To withdraw from methadone, buprenorphine doses of 2 to 4 mg/day have been substituted for 20 to 30 mg/day of methadone without precipitating substantial withdrawal symptoms. Buprenorphine may then be gradually tapered over several days with rapid introduction of naltrexone and withdrawal symptoms ameliorated by clonidine (Stine & Kosten, 1992). Buprenorphine has been given as alternate-day dosing, with twice the daily maintenance dose every other day (Amass et al, 1994a) or triple the daily maintenance dose every third day or quadruple the daily maintenance dose every fourth day (Petry et al, 2000). In 1 study, patients taking buprenorphine for withdrawal experienced less severe withdrawal symptoms than patients taking clonidine and naltrexone combination (O'Connor et al, 1997).

a) Butorphanol (Stadol(R)), an opioid agonist-antagonist, is marketed as a parenteral or nasal spray that, when given as an undiluted nasal spray, will precipitate withdrawal symptoms in opiate-dependent subjects. In 1 study, butorphanol nasal spray was diluted initially to 40% and gradually changed to 10%. Dosing frequency ranged from every hour to twice daily initially, and gradually decreased from 4 times daily to 3 times weekly before stopping (Glatt, 1999).

a) Methadone is used for both withdrawal and maintenance therapy. However, it produces dependence and withdrawal results upon abrupt discontinuation. The National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction has recommended that unnecessary regulation of methadone maintenance therapy (MMT) be reduced, and that methadone be more readily available for treatment of addicts, particularly pregnant women (Anon, 1998a).

a) TRAMADOL VS METHADONE: Tramadol, a centrally acting analgesic with a partial affinity for the mu opioid receptor, has a low potential for abuse and dependency, a short half-life, and a low risk of respiratory depression and cardiac toxicity. In a double-blind, randomized clinical study, 70 patients who were undergoing heroin detoxification were randomly assigned to either receive methadone 20 mg 3 times daily (n=35) or tramadol 200 mg 3 times daily (n=35). Objective Opioid Withdrawal Scale (OOWS) was used to assess the severity of the opiate withdrawal syndrome of patients. This scale contains 13 observable physical signs (yawning, rhinorrhea, piloerection, perspiration, lacrimation, mydriasis, tremors, hot and cold flushes, restlessness, vomiting, muscle twitches, abdominal cramps, anxiety), rated as present or absent by an independent observer, on days 1, 4, 6, 10, and 14. Overall OOWS scores did not differ significantly between 2 groups (p=0.11). In addition, there were no significant differences in side effects scores for dizziness, somnolence, ataxia, constipation, nausea, seizures, and respiratory depression between the 2 groups, except for perspiration which was significantly higher in tramadol treatment group (p=0.02), and pain, which was significantly higher in the methadone treatment group (p=0.01) (Zarghami et al, 2012).

a) Naltrexone is an opioid antagonist used to prevent relapse through use of daily doses. It offers the advantage of treatment with no addictive potential or tolerance. The usual naltrexone dose to block opioid effects is 50 mg/day orally for several weeks, followed by a schedule of 3 doses per week: 100 mg on Monday, 100 mg on Wednesday, and 150 mg on Friday. Before initiating therapy, the patient should be opioid-free for at least 1 week to avoid a withdrawal reaction (O'Connor & Fiellin, 2000; Prod Info ReVia(R), naltrexone hydrochloride, 1999; Willette, 1982).
b) Naltrexone depot (Depotrex(R)) is being evaluated for its longer-lasting opioid antagonist effects in heroin users. Either 192 mg or 384 mg of depot naltrexone was injected 1 week after detoxification from heroin. Up to 25 mg of heroin was given intravenously daily on Monday through Friday each week for 6 weeks. The low and high dose of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Naltrexone plasma levels remained above 1 nanogram/milliliter (ng/mL) for about 3 and 4 weeks after dosing with 192 mg or 384 mg, respectively. No adverse effects were noted. The dose of heroin that would override the blockade during the first 6 weeks after naltrexone depot was not determined (Comer et al, 2002).
c) DRONABINOL: A double-blind controlled trial was performed to evaluate the efficacy of dronabinol (a cannabinoid receptor type 1 partial agonist) in reducing opioid withdrawal and increasing retention in treatment with extended release naltrexone (XR-naltrexone). Opioid dependent patients who were undergoing inpatient detoxification and naltrexone induction, were randomly assigned to receive either dronabinol 30 mg/day (n=40) or placebo (n=20), while inpatient and for 5 weeks after discharge. All patients were administered a dose of XR-naltrexone injection prior to discharge and for another 4 weeks later. Dronabinol group had lower severity of opioid withdrawal during inpatient phase compared with the placebo group. However, there were no significant differences between the rates of successful induction to XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%). Ratings of insomnia and anxiety were significantly lower in 32% of patients who smoked marijuana regularly during the outpatients phase and were more likely to complete the 8-week trial (Bisaga et al, 2015).

a) Naloxone has been given as a challenge test to determine whether an alleged opiate-dependent person is indeed physically opiate dependent. Naloxone may be administered as 0.4 to 0.6 mg IV, IM, subcutaneously or sublingually; watch for signs of opiate withdrawal syndrome; if no effect, patient not physically dependent; to relieve withdrawal symptoms, give 15 to 30 mg of morphine. In addition to a challenge test, naloxone may be given as opiate antagonist precipitated withdrawal in order to compress detoxification into as short a time period as possible. Clonidine or buprenorphine may be given during this procedure to lessen withdrawal symptoms (Mendelson et al, 1999; Fishbain et al, 1993; Preston et al, 1990).

a) A randomized controlled trial of 106 treatment-seeking heroin-dependent patients (aged 21 through 50 years), comparing 3 different treatment interventions (anesthesia-assisted vs buprenorphine-or clonidine-assisted heroin detoxification and naltrexone induction), did not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction. All 3 treatment interventions had comparable mean withdrawal severities. Although all 3 groups had similar rates of completion of inpatient detoxification, the anesthesia- and buprenorphine-assisted detoxification interventions had significantly greater rates of naltrexone induction (94% anesthesia, 97% buprenorphine) compared with clonidine-assisted detoxification (21%). Over the course of the study (12 weeks), treatment retention did not differ significantly across intervention groups (7 of 35 (29%) in the anesthesia-assisted group, 9 of 37 (24%) in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted group). The risk of dropping out was reduced significantly by induction with 50 mg of naltrexone (odds ratio, 0.28; 95% confidence interval, 0.15 to 0.51). Three potentially life-threatening adverse events were observed in anesthesia-assisted group (Collins et al, 2005).
b) One method described for rapid detoxification from opioids has used an infusion of naloxone 4 mg for a period of 5 hours, using controlled ventilation during general anesthesia, induced and maintained with midazolam, propofol, and atracurium. Cardiovascular and respiratory monitoring were performed throughout the procedure. Anesthesia was maintained for 1 hour after stopping the naloxone infusion (Lorenzi et al, 1999). Clonidine infusions, titrated to attenuate withdrawal symptoms, have also been used during weaning and after extubation (Kienbaum et al, 2000).
c) Hamilton et al (2002) described serious complications of a method (unapproved) of ultrarapid opioid detoxification with subcutaneous naltrexone pellets inserted during anesthesia. The risks of this procedure are great. Complications have included acute lung injury (pulmonary edema) prolonged withdrawal, drug toxicity, withdrawal from cross-addiction to alcohol and benzodiazepines, variceal rupture, aspiration pneumonia, and death (Hamilton et al, 2002).

a) Calcitonin nasal spray has been given in doses of 200 IU/day to patients following abrupt withdrawal of low-dose methadone. Withdrawal symptoms were alleviated in a small study group (n=20) as compared with controls with no drug treatment for withdrawal, without increasing B-endorphin levels. An inhibitory action on insulin secretion was noted during calcitonin therapy (Vescovi et al, 1992).

a) Ibogaine, an alkaloid that is not a conventional dopamine or opioid agonist or antagonist or an amine reuptake inhibitor, has been given orally for alleviation of acute opioid withdrawal syndrome. Ibogaine has affinities for CNS receptor binding sites including NMDA, kappa opioid, and sigma and nicotinic receptors. Its exact mechanism of action is unknown.

a) Ascorbic acid (vitamin C) has been given orally in high doses (300 mg/kg/day) with vitamin E (5 mg/kg/day) for a minimum of 4 weeks to ameliorate withdrawal symptoms (in addition to conventional symptomatic therapies) in heroin abusers. At high concentrations, ascorbic acid has been shown to inhibit the endogenous opioid degrading metalloenzyme and increase endorphin levels. Further studies are needed to clarify dose and time-dependent effects of ascorbic acid treatment and establish its safety and effectiveness (Evangelou et al, 2000).

a) Acetorphan, an enkephalinase inhibitor, appears to protect endogenous enkephalins via inhibition of the peptidases responsible for their inactivation, thus constituting a new approach to the treatment of opioid withdrawal syndrome. Acetorphan was demonstrated to be at least as effective as clonidine for treating opiate withdrawal symptoms. In a double-blind, placebo-controlled study, 19 confirmed opiate addicts received intravenous acetorphan 50 mg twice daily (N=10) or oral clonidine 0.075 mg every 4 hours and then intravenous or oral placebo as appropriate. Objectively, acetorphan controlled the symptoms of withdrawal to a greater extent, but subjectively both agents were considered equal (Hartmann et al, 1991).

a) METHADONE MAINTENANCE: An inverse relationship exists between methadone plasma concentrations and withdrawal severity and pupil diameter. Clinically significant withdrawal results from a more rapid decline in methadone plasma concentration. Trough concentrations are often greater than 200 nanograms/milliliter (ng/mL) in these patients (Dyer et al, 1999).
b) METHADONE MAINTENANCE: Borg et al (1995) reported methadone plasma levels less than 150 ng/mL were associated with 4 or more withdrawal symptoms in 40% of patients. Of patients reporting fewer than 4 symptoms, 90% had methadone levels greater than 150 ng/mL.