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Other Substance Use Disorders
In Methadone Treatment - - -  
Prevalence, Consequences,
Detection  And Management
Of  Multiple Substance Abuse
Among  Methadone Patients.
       

Among methadone maintenance patients, the use of other drugs is common.  The chemical substances abused by methadone patients during treatment include those that are legally available - tobacco and alcohol - as well as drugs that can be obtained only on the illegal market--heroin and cocaine.  The use of oral prescription medications is also seen in methadone patients - included, but not limited to benzodiazepine tranquil-izers.   Finally, new compounds surface periodically within the panoply of drugs favored by methadone patients, clonidine being a recent example, so patients must always be alert to new trends in drug use.

This section  reviews the prevalence, consequences, and detection methods for drugs commonly used by patients during methadone treatment. It focuses on heroin, cocaine, benzodiazepines, alcohol, marijuana and tobacco and makes recommendations for the clinical management of patients using various drug combinations.


There are medical, psychological, and behavioral risks inherent in using all drugs of abuse, and these risks continue when methadone patients use licit and illicit drugs of abuse during treatment.  This section provides a brief overview of some of the risks and adverse consequences that methadone patients face when they continue to use chemical substances during treatment.


Although Heroin has no direct toxic effects, there may be several important adverse consequences of continued heroin use during treatment. One consequence, if use is by the intravenous route, is the potential for HIV infection, hepatitis B and C infections, abscesses and other infections when drug preparations or intravenous equipment is contaminated.  A second potential risk, which is currently based on speculation rather than research, is that patients who continue to use heroin will tend to become more physically dependent through exposure to the added short-acting opiate.  This dependency in turn could result in increasing levels of withdrawal discomfort and the need to continue the use of short-acting opiates for withdrawal symptom relief.  In this scenario, increasing the methadone dose could be a beneficial treatment strategy, because suppression of the excess withdrawal symptoms should result.  Continued association with drug users and a drug-using lifestyle could be listed as a final adverse consequence of heroin, as well as cocaine, use during treatment


Heavy alcohol use among opiate addicts has been associated with health problems, increased mortality, and disruptive behaviors at the clinic. Other common-alcohol-related problems include blackouts, aggressive or violent behaviors, arrests, accidents, loss of employment, disruption of family life, and deterioration of mental and physical health. In one study in which a sample of methadone-maintained problem drinkers were enrolled in an alcoholism treatment project, half of the subjects had been hospitalized with an alcohol-related illness in the three months prior to participation.(Ling et al. 1983) . Liver disease is the best known and most common complication associated with excessive drinking.  However, alcohol use is well known to produce toxic effects on other organs and can result in both acute and chronic cognitive impairment, as well as heart, kidney and blood disorders.  Alcohol use is a leading cause of death in methadone patients, estimated in different studies to account  for 18-60 percent of all mortalities (see Bickel, Marion, and Lowinson 1987).  In a 12-year follow-up study of individuals previously enrolled in drug abuse treat-ment, heavy drinkers died at a rate seven times higher than an age-adjusted general population (Sells and Simpson1987).  Alcohol use is also a strong contributing factor to premature treatment discharges and has been estimated to account for about 25% of discharges from methadone programs, primarily because its association with absenteeism and disruptive behavior at the clinic (Bickel and Amass 1992). 


Alcohol deserves special mention as a secondary drug of choice.  Remarkably, in the past century, alcohol and heroin have been mistaken as potential treatments for one another (Siegel 1986), and iatrogenic dependence in both directions has been the result of good intentions.  The two drugs have some common analgesic effects; experimental evidence shows that opioid antagonists, (naltrexone) may diminish alcohol intoxication (Nyers et al. 1986), and opiate peptides or receptors may be modulated by alcohol use (Trachtenburg and Blum 1987).  Animal studies indicate that alcohol use produce increased methadone concentrations in the brain (Lane et al 1985).  Most importantly, alcohol and related drugs are CNS depressants that are potentiated by methadone and can produce coma and death in overdose.   When correctly prescribed, disulfiram (Antabuse®) is a viable action for an adjunctive management of alcohol use in the patient in an Methadone Maintenance Treatment Program.  Alcohol dependence may become an even more critical issue following completion of Methadone Maintenance Treatment, with studies indicating a number of patients becoming seriously ill with alcohol dependence, and even dying from cirrhosis, despite remaining opioid abstinent (Joseph and Appel 1985). There are other patients who, while attempting to undergo  a gradual withdrawal from methadone, will switch to alcohol.


Problems associated with benzodiazepine use can include sedation, memory impairment, overdose, and physical dependence.  Although tolerance develops to the sedative effects of these drugs, the use of benzodiazepines may be may be a factor in road accidents, particularly when they are used in combination with other sedative drugs such as alcoholMemory impairment is one of the most striking adverse effects of benzodiazepines (see Curran 1991), and it is not clear how much tolerance develops to this effect. Clinically, memory impairment could be disruptive or dangerous to the extent that a person may forget important events or information, or engage in risky behaviors while under the influence of drugs. While an overdose with benzodiazepines alone is generally not lethal, an overdose of a benzodiazepine combined with another sedating drug (including methadone) can be fatal.  Thus, benzodiazepines are routinely found in toxicology screens of suicide victims, or attempters, and suicide risk should be closely assessed and monitored in methadone patients who are taking benzodiazepines. 

Perhaps the most prominent and relevant risk associated with benzodiazepine use in drug-abusing population is that of physical dependence and withdrawal symptoms following discontinuation.  When regular use of benzodiazepines is discontinued, patients can experience rebound anxiety and agitation, insomnia, tension, sweating, tremulousness, ringing in the ears, increased sensitivity to noises and to light, and sensory and perceptual distortions (Busto et al.1986). In cases of severe depend-ence, withdrawal delirium and and seizures, (like those seen in severe alcohol withdrawal) may be observed. The extent and timing of symptoms will depend in part on the amount and duration of previous use as well as the type of benzodiazepine being used.  Because of the potentially dangerous symptoms that can appear, benzo-diazepine detoxification should be conducted only under medical supervision (Alling 1992). 


Cocaine has substantial medical risks (reviewed in Benowitz 1993).  The most serious risks are related to intense central nervous system stimulation and vasoconstriction, which can result in severe hypertension.  This in turn can produce serious conse-quences such as aortic rupture or restricted blood flow to organs that can lead to heart attacks and damage to the kidneys and intestines.  Pregnant abusers who use cocaine can experience spontaneous abortions and placental abruption. Most deaths result from cocaine use are sudden and occur before medical help can be found.  However, despite these potentially serious complications, cocaine use may actually be associated more with traumatic deaths and injuries (including homicide, suicide, and accidents) than with medical complications. Cocaine intoxication can also produce mental confusion and other symptoms including anxiety, panic attacks, agitated delirium, and paranoid psychosis.  Symptoms produced by cocaine, including chest pains and mental confusion, are a common cause of visits to inner-city emergency rooms.


Like alcohol, the other depressants pose increased risks for toxicity and overdose with methadone.  Alcohol and CNS depressants can induce life-threatening withdrawal reac-tions, which are not treated by methadone.  Signs and symptoms of withdrawal include elevated body temperature, hypertension, rapid pulse, confusion, hallucinations, and intractable seizure.  When depressant drug dependence is diagnosed in the methadone-maintained patient, methadone should be continued (and the patient monitored for a possible need for increase), and the depressant should be withdrawn as clinical circumstances dictate. Detoxification from depressants may require inpatient treatment to be effective, and methadone maintenance treatment should be continued during the inpatient stay.  Additionally, a history of seizures during sedative-hypnotic-anxiolytic or alcohol withdrawal is an absolute indication for inpatient medically managed detoxification.     



Initial hopes that Methadone Maintenance Treatment  would reduce cocaine use have been discarded on the basis of discouraging reports.  A group from San Francisco General Hospital found that 24 percent of patients began or increased cocaine use after beginning methadone maintenance treatment (Chaisson et al. 1989).  Kosten and coworkers (1987) conducted a 2.5 year followup study that showed the amount of cocaine use had been only minimally reduced by methadone maintenance, and the number of patients who used cocaine weekly actually doubled.

One reason that comorbid stimulant and opioid use is prevalent is that the two drugs counteract each others' side effects. This interaction accounts for the popularity of the heroin and cocaine combination known as "speedball." Heroin "mellows out" cocaine -induced agitation, while cocaine allows the addict to experience opioid euphoria without the "nod."  The temporal relationship of other drug use (whether heroin or, for example, cocaine is the primary drug or drug of choice) is important in assessing the individual's needs. Primary cocaine addicts may need specific attention given to the cocaine dependence early in treatment. Clinical experience suggests that primary heroin addicts will not use cocaine prior to getting an adequate "fix" of heroin. Cocaine used alone causes sufficient agitation that the heroin addict may misperceive cocaine as precipitating opioid withdrawal when not pretreated with heroin.

Primary cocaine addicts, on the other hand, will use cocaine first and take heroin to ameliorate, (to improve) the adverse effects of the "crash."  Primary cocaine addicts can, over time and given enough use of heroin, develop a physiologic dependence upon heroin and require methadone maintenance as treatment.  It is not appropriate to deny a heroin addict treatment in a methadone maintenance program because of the presence of other addictions; a rational treatment plan that integrates measures for treating all psychoactive agents should be devised.

A number of research initiatives on the so-called anticraving drugs showed early promise (tricyclic antidepressants, Ritalin, buprenorphine...) but the premise has not yet trans-lated into daily clinical usefulness.  Tricyclic antidepressants had been explored exten-sively (Gold et al. 1992); McElroy et al.) but early results have not been replcated.  At this time, tricyclics are a subject for further research and treatment for patients with these medications is in the research domain. 


Adverse effects of marijuana include motor incoordina-tion and memory impairment.  These effects may interfere with the patient's ability to perform tasks and could contribute to accidents.   Marijuana can also have adverse psychologic consequences, including anxiety and panic attacks, perceptual distortions, and in extreme cases, toxic psychosis. The primary physiologic effects of marijuana are increased heart rate, in-creased appetite, and bloodshot eyes. Although increased heart rate could be a problem for persons with cardiovascular disease, dangerous cardiovascular reactions to marijuana are rare. A well- confirmed danger of  marijuana, however, is its effects on the lungs.  Marijuana smoke contains the same carcinogens as tobacco smoke, usually in somewhat higher concentrations. Marijuana is inhaled deeply and held in the lungs longer than tobacco smoke, so there can be an increased risk of lung diseases including bronchitis, emphysema and lung cancer. These effects add to the potential damage caused by nearly universal cigarette smoking in the methadone population. Little evidence has emerged linking marijuana use during methadone treatment with the use  of other illicit drugs or with poor treatment response. By contrast, other secondary drugs of abuse, most notably cocaine  and benzodiazpines, are clearly associated with higher rates of heroin use, greater risk-taking behaviors, and poor treatment response.

Cannibis - Marijuana, hash, hemp, pot    Psychotropic Agent    - Interaction proposed due to common CYP3A4 pathway with methadone (Harrington et al. 1999). 


Tobacco use is associated with elevated risk of morbidity and mortality in the general population, with over 400,000 persons dying annually from smoking-related causes, including heart attack, stroke, lung cancer, and other chronic lung diseases.  It would be expected that these patients have a similar elevated risk of mortality related to their cigarette smoking as has been demonstrated for the general population.  Even if the drug abusers discontinued all of their illicit drug use and decreased their alcohol consumption, they would still be at risk for premature death and disease from their cigarette smoking.

 


If you are a methadone patient and are taking multiple drugs, please take the time to read  "Ways In Which Drugs Interact" for your own safety.  It is a very short course on "Drug Interactions". I have tried to use the simplest form to describe how they work in your body.  Life is too short to die because you lacked know-ledge.  Knowledge is power, therefore if you are going to use multiple drugs and consume alcoholic beverages ~ take the time to read all I have written on "Drug Interactions".  Therefore, after attaining the knowledge ~you will have the power to take control of your drug use wisely and of your life and may be around to enjoy another year with us.   Thank You. 

There are many ways in which drugs can interact with each other within the body to cause problems.  Many adverse interactions happen because the drugs do different things that interfere with their mechanism, or the way they work.  Many others occur because of the way that the drugs are stored or distributed within the body or the way in which they are eliminated from the body. The following interactions are described:

 ABSORPTION                       DISTRIBUTION                  PROTEIN-BINDING                                                                                                          


In order for a drug to work, it must be free and in the bloodstreamThus, if it is taken orally, the drug must be absorbed from the gastrointestinal (GI) tract into the blood-stream. Sometimes, two drugs are absorbed into the body in the same way and so interfere with each other's absorption by competing for transport sites into the body. 

In the same way, some drugs decrease the absorption of other drugs by binding to them in the stomach or intestine and preventing their absorption into the body.  For example, sucralfate (Carafate®), a drug used to promote healing of the  stomach lining,  binds to many drugs in the digestive tract and prevents or decreases their absorption; the tetracycline drugs (tetracycline, doxycycline, minocyline, ...), if taken with meals or mineral supplements (which contain iron, calcium, and magnesium), bind to these minerals in the intestine and cannot be absorbed into the body.  

The acidity or alkalinity (pH) of two drugs taken together can influence the absorption of a drug as well.  For example, antacids or histamine blockers (cimetidine, ranitidine), which decrease stomach acidity, will decrease the amount of aspirin or other acidic drugs absorbed into the body,  this decreasing the drug's effectiveness. (Acidic drugs are absorbed well in the acid environment of the stomach.  Antacids decrease the acidity of the stomach and thus decrease the absorption of acidic drugs.)  Changes in body pH due to the ingestion due to the acidity or alkaline drug or substance can influence the rate of clearance of the drug as well (see below).

Absorption of a drug is also influenced by the route of administration .  Drugs injected intramuscularly are absorbed more slowly than drugs injected intravenously (which are technically not absorbed at all since the drug goes directly into the bloodstream).  Including a vasoconstrictor, or local anesthetic, such as procaine, will reduce the rate of absorption even further, allowing more drug to be injected with a slower absorption rate ('long-acting" formulations).        


Once the drug is in the bloodstream, it disseminates throughout the body, or is dis-tributed.  Part of the drug will be free in the plasma  (this is the drug that will be actually working in the body).  The rest must be stored in some way, such as bound to plasma proteins, or stored in fat. Binding of the drug to plasma proteins stabilizes the drug and also keeps it broken down by the liver or filtered out or excreted by the kidneys (the proteins are too big to be filtered out).  Remember that a drug in order to work, must be free in the plasma---a stored drug is not available to work.   The more free drug in the plasma, the greater is the effect and there is greater potential for toxicity.


Many drug interactions occur because two or more drugs bind to the same plasma proteins. The one that binds the tightest and the fastest "wins" leaving the "loser" floating in the plasma.  This results in too much of the "loser" drug as free drug in the plasma.  Since free drug is available to work in the body, this drug may cause toxic effects.  

"Remember for a drug to work, it must be free and in the bloodstream."   

In addition, because the free drug is more quickly metabolized or filtered out by the kidney, this drug will be eliminated from the body faster, as well.   When two drugs that both bind extensively  to plasma proteins are taken concurrently, the doses must be adjusted to reflect the change in plasma free drug concentrations.  An example of a drug that is highly protein bound is warfarin (Coumadin®).  This drug has protein-binding  interactions with many drugs.                                                  


Whenever a patient takes a drug, that drug is designed to do its job and leave.  The body eliminates the drug after a period of time by breaking it down with enzymes (metabolism) in the liver and/or using the kidneys to filter it out of the blood and dump it into the urine.  Drugs that are metabolized may go into the bile and out through the intestines, or, if the actions of the enzymes in the liver make them water--soluble (so that they can be dissovled easily in water), they may go out through the urine. Some drugs are not metabolized; if they are soluble enough in water, they may go directly out in the urine. 

A very important drug reaction occurs when more than one drug is being metabolized at the same time  (this includes drugs such as alcohol).  Some drugs interact by competing with each other for the same enzyme or altering the activity of a liver enzyme.  Enzymes are proteins that break down drugs.  Many drugs are metabolized by a particular group of enzymes called cytochrome 450.  Drugs such as cimetidine, (Tagamet®) alter the activity and amount of these enzymes, which decreases the metabolism of other drugs that use it.  This means that the drug levels in the blood will increase as the patient keeps taking the prescribed doses.     

An important thing to consider is a patient's age. Be-cause drugs are cleared out of the body by the liver and kidney and the functions of these organs decrease with age, the dosage of the drug must be adjusted to compensate.  Another important factor, especially when assessing drugs eliminated by the liver, whether the patient is an abuser of alcohol or has preexisting liver damage (from hepatitis).  Any existing damage to the liver could decrease the rate of clearance of the drug, causing the blood levels of drug to build up to toxic levels  over time.                                                               

                      

                          DRUG TOXICITY AND INTERACTIONS

All drugs are, to some extent, poisons and have harmful effects. The dosages established for the patient are designed to minimize the harmful effects while maximizing  the beneficial effects. However, taking more than one drug concurrently may cause a problem; sometimes one drug can set the stage for the harmful effects  (toxic effects) of another.  For instance, drugs like isoproteronol (a sympathetic agonist at beta receptors) act on the heart to increase heart rate and increase electrical conduction through the heart tissue.  Too much can cause tachycardia (rapid heart rate) and arrhythmias (irregular heart rate).   Thyroid drugs sensitize the heart to the effects of norepinephrine and epinephrine which are produced under stress (and have effects on the heart similiar to isoproterenol).

Taking thyroid hormone (or just being hyperthyroid) while taking a drug like isoproterenol could increase the sensitivity of the heart to the toxic effects of the drug and result in severe arrhythmias.   Arrhythmias (irregular heart rate) can result from stress, caffiene, tobacco, alcohol, diet pills, cough and cold medi-cine.   

Drugs like furosemide and thiazide diuretics cause a large amount of potassium excretion.  The heart is very sensitive to potassium, and particularly when other drugs alter potassium levels are taken concurrently (for example, digitalis glycosides), the loss of potassium can lead to severe arrhythmias.


Drugs  that produce the same physiological effects may behave differently when taken together. For example, if two drugs both lower blood presssure by the same mechanism (for example, blocking calcium channels) and both are seen to lower systolic pressure by 5%, then by taking both drugs concurrently, we would expect a 10% decrease in systolic pressure.  This is called an additive effect the amount of effect of one drug is adding to that of another.  If instead these two drugs did not work by the same mechanism -- say, one drug blocked calcium channels, reducing systolic pressure by 5%, and the other blocked norepinephrine receptors (also reducing systolic pressure by 5%) -- taking both drugs concurrently might produce a decrease of 15%.  This is called synergism ~ two drugs taken together producing a physiological effect which is much greater than the effects of each drug added together ( 5%+ 5% = 10%, not 15%).  In contrast, a drug may interfere with the actions of another, reducing the physiological effect.  This is called antagonism. 

Some drugs produce similiar toxic effects and should not be used together.  For example, furosemide and streptomycin both produce ototoxicity ( inner ear toxicity) furosemide lowers the fluid volume in the inner ear reducing stimulation of the auditory nerve, and aminoglycoside antibiotics, such as streptomycin, are directly toxic to the auditory nerve.  When these drugs are taken alone, the effects are manageable; however, when taken concurrently the effect of the auditory nerve more than doubles.  These drugs synergize to produce a very large detrimental effect on the ear, with much more ototoxicity than would be expected.

 Another common example is the interaction between a central nervous system  (CNS) depressant and an antihistamine.  Antihistamines produce a small amount of CNS depression, some more than others.  However, when antihistamines are taken with another drug that produces CNS depression, such as anticonvulsants or antipsychotics, the effect can be lethal.  The same is true with ethyl alcohol, which is an extremely potent CNS depressant.  If alcoholic beverages are taken with drugs such as antiseizure medications, antipsychotics, antidepressants, and similiar drugs that produce CNS depression (particularly barbiturates, which can be lethal by themselves, if abused), the central and autonomic nervous systems can be depressed to an extent that they are unable to function, and death could result.  Since the depressant effect is so much greater when both drugs are taken concurrently, this is a synergistic reaction

Some medications initially interact with methadone to cause sedation, but then the opposite occurs, and they can cause withdrawal symptoms. May cause additive CNS depression.     

These medications include1.  Benzodiazepines  such as:

Alprazolam -- Xanax®-              Diazepam -- Valium®

Clorazepate Dipotassium-- Apo-Clorazepate®, Gen-XENE®, Novoclopate®, Tranxene® , Tranxene-SD®, Tranxene-T-Tab®

Estalozam-- ProSom®                  Oxazepam--Serax®

Flurazepam --Dalmane®               Clonazepam--Klonopin®, Rivitrol®

Midazolam-Hydrochloride--Versed® is mostly used as an injection for sedation before surgical procedures.

Triazolam--Halcion®.                    Chlorodiazepoxide--Librium®

Temazepam--Restoril®                    Prazepam  --Centrax®

Alcohol is an extremely potent central nervous system depressant.  Please use it wisely when taking in combination with other medication.                                                                     

 2. Alcohol  --   Ethyl alcohol is an extremely potent central nervous system depressant.  If alcoholic beverages are taken with drugs such as antiseizure medications, antipsychotics, antidepressants, and similiar drugs that produce central nervous system depression, particularly barbiturates, which can be  lethal by themselves if abused , the central and autonomic nervous can be depressed to an extent that they are unable to function.  Since the depressant effect is so much greater when both drugs are taken concurrently, this is a synergistic reaction.  

Barbiturate sedatives and/or hynotics taken with methadone , if both drugs are taken concurrently will produce a synergistic action, as described above.  P450 enzyme induction. (Kreek 1986); phenobarbital can cause sharp decrease in methadone (Gourevitch 2001) .  Methadose dose increase usually required.                                                                                   

3. Barbiturates include the following:

Luminal Sodium®  ---   Phenobarbital Sodium                  Phenobarbital can cause sharp decrease in methadone.                                         

Seconal®  --- Secobarbital Sodium    Nembutal® --- Pentobarbital

Tuinal® ---  Amobarbital/Secobarbital

Aprobarbital®  ---   No Trade Names    Mebaral® --- Mephobarbital

Butalbital  ---  Bancap®, Axotal®, Butal Compound®, Bucet®, Fiorcet®, Fiorinal®, Fiorinal #3®

Butabarbital --- Butalan®, Butacaps®, Sarisol®  Butisol®

4.  Some medicines slow the metabolism of methadone. Sometimes people will feel the effect of methadone more strongly when they take these medications, and sometimes they experience withdrawal symptoms when they stop taking these medications: 

(A) Antidepressants include the following: (Tricyclic  Antidepressants) Possible increased TCA toxicity; uncertain effect on methadone; increase or decrease.

Amitriptyline - Elavil®                        Desipramine - Norpramin®

Imipramine - Tofranil®                        Nortriptyline - Pamelor® 

The drugs may not be all-inclusive of drugs/brands that might be contraindicated or interact with methadone.                                            .                        

Warning:  Tricylic antidepressants has been
associated with cardiac rhythm disturbances,
(prolonged QTc interval and/or torsade de 
pointes) and should be used cautiously
with methadone!!!.     

          

For lastest listings see: 

Click Here                         http://www.QTdrugs.org

 (B)   H2-receptor antagonist for GI disorders:

Cimetidine ---Tagamet®

Omeprazole ---Prilosec®   Treatment of acid-related GI disorders.  In animal studiies, possibly affects methadone absorption (Strang 1999).  

(C)  Selective Serotonin Uptake Inhibitors-affect chemicals in the brain that have become unbalanced and cause obsessive -compulsive disorder; used to treat obsessive-compulsive disorders involving reoccuring thoughts and actions;can be used for depression.

Fluoxetine--Prozac®                                 Fluvoxamine--Luvox® 

Paroxetine-Paxil®                                     Nefazodone-Serzone®

Sertraline-Zoloft®

The above drugs has been associated with cardiac rhythm disturbances, (prolonged QTc interval and/or torsade de pointes) and should be used cautiously with methadone.     
  Use Serotonin Reuptake Inhibitors cautiously with methadone.                                 

(D)  Antifungal Agents

Ketoconazole  -   Nizoral®                                                                        Has been associated with cardiac rhythm disturbance (prolonged QTc interval and/or torsade de pointes) and should be used cautiously with   methadone.                                                               

(E) Antifungal Antibiotic 

Fluconazole - Diflucan®

Warning!!! The drugs listed below may
raise serum methadone levels
and/or
increase the effects of the ................
methadone.   Your dose of methadone
may need to be lowered temporarily.         
     

(F)  Ciprofloxacin-Cipro®                      Quinolone Antibiotic

(G)  Macrolide Antibiotics-Predicted due to strong inhibition of CYP3A4 enzyme.  Cardiac and metabolic effects not expected with azithromycin (Eap et al. 2002).  Anti-infective.

Erythromycin- EES® Erythrocin®                Clarithromycin-Biaxin®

(H)  Troleandomycin-TAO®             Antibiotic (similiar to erythromycin).

(I)  Urinary Alkalinizers -Treatment of kidney stones, gout therapy.  Alkaline (higher pH) decreases methadone excretion by kidneys. (Kalvik et al. 1996). 

Sodium Bicarbonate -Bicitra®,Polycitra®

(J)  Alcoholism Treatment  - Sedation noticed with higher doses of disulfiram (Bochner 2000).

  Disulfiram-Antibuse®

(K)  Ethanol  - Acute Use  (Euphoric, sedative)  Competition for P450 enzymes (Quinn et al.)

Wine, beer, Whiskey...

(L)  Migraine Treatment - CYP3A4 enzyme inhibition (Van Beusekom and Iguchi 2000),

Dihydroergotamine - D.H.E.®, Migranal®

(M)  Diazepam-Valium®, Dizac®, Valrelease®  Control of anxiety and stress.  Mechanism undetermined (Eap et al. 2002) and effect sporadic (Levy et al. 2000).

(N)  Grapefruit- juice or whole fruit      Inhibits intestinal CYP3A4 (Hall et al. 1999) and PgP (Eap. et al. 2002i) This effect is not expected with other fruits/juices (Karlix 1990.

(0)  "natural' supplements" - Herbal products used for gastrointestinal therapy, Immune system enhancement, others.  Not stuidied specifically with methadone; predicted potential effect  due to strong CYP3A4 enzyme inhibition (Scott and Elmer 2002, Van Beusekson and Iguchi 2001).

Uncaria tomentosa -Cat's claw ®                      Matriacaria recutita  -Chamomlle®

Echinacea angustifolla-Echinacea®                  Hydrastis canadensis  Goldenseal®

Quercetin- (May be ungredient in various product brands).

(P)  Delavirdine-Rescriptor®   NNRTI antiretroviral  Predicted effect due to CYP3A4 enzyme inhibition (Gourevitch 2001).

(Q)  Mocloemide - Auroxix®,Manerix®            MAO Inhibitor (antidepressant) 
Expected due to CYP2D6 and/or CYP1A2 Inhibitio (Eap et al. 2002).

(R)  Verapamil - Calan®, Covera-HS®, Isoptin®        Cardiac drug; Ca++ -blocker.  Predicted  effect due to CYP450 enzyme inhibition.

The medications below cause the liver   
to metabolize methadone more quickly
and may cause a need for an increased
  
methadone dose!!!     
                                                              
 News Alert!!!  May need to raise dose
temporarily--see your physician if with-
drawal symptoms.

Abacavir (ABC) - Ziagen®       NRTI antiretoviral       Methadone level decreased; also reduces ABC peak concentration (Gourevitch 2001).

Amprenavir - Agenerase®       Pl antiretroviral          CYP3A4 enzyme induction may decrease methadone levels  (Chrisman 2003;Eap; et al.2002).  Amprevair also may be reduced. (Faragon and Piliero 2003).   

Carbamazepine - Atrotol® Tegretol®       Anticonvulsant for epilepsy and trigeminal neuralgia.  Strong CYP3A4 enzyme induction may cause withdrawal. Effect not predicted with valproate (Depakote; Bochner 2000; Saxon et al. 1989). 

Cocaine - Crack,coke,others     Illicit Stimulant      Accelerates methadone elimination (Moolchan et al.).

Dexamethasone -  Decadron® Hexadrol®       Corticosteroid      CYP3A4 enzyme inducer (Eap et al. 2002).

Efavirenz - Sustiva®     NNRTI Antitetroviral     Due to CYP3A4 induction; methadone withdrawal is common and dose increase usually required (Eap et al.2002, McCance- Katz et al. 2002).

Ethanol.-   (Chronic Use)          wine, beer, whiskey     Euphoric, sedative       P450 enzyme induction.  (Quinn et al. 1997).

Fusidic acid  - (systemic steroidal)      Antibacterial     CYP3A4 enzyme induction (Eap et al. 2002; Van Beusekom and Iguchi2001).

Heroin - smack, scat, others    Illicit Opioid     Decreases free faction of methadone.

Lopinavir + Ritonavir  -  Kaletra®     PI antiretroviral     Withdrawal symptoms may occur requiring methadose dose increase.  Latest research suggests effect is not seen with ritonnavir (Chrisman 2003; McCance - Katz et al. ). 

Nelfinavir - Viracept®   Pl antiretroviral     CYP3A4 and PgP induction (Eap et al.2002) but clinical withdrawal is rare (McCance-Katz et al. in press 2003)  Interaction also may mildly decrease nelfinavir (Chrisman 2003).

Nevirapine - Viramune®      NNRTI antiretroviral      CYP3A4 enzyme induction may precipitate opioid withdrawal.

Phenytoin - Dilantin®      Control of seizures.        Sharp decrease in methadone due to CYP3A4 enzyme induction (Eap. et al. 2002).

Rifampin (rifampicin) and rifampin/isoniazid - Rifadin®, Rimactane®, Rifamate®     Treatment of pulmonary tuberculosis.     Induces P450 enzymes; cases of severe withdrawal reported (Eap et al. 2002; Kreek 1986).  Effext not seen with rifabutin (Mycobutin:  Gourevitch 2001; Levy et al. 2000).

Spironolactone -  Aldactone®      K+ sparing diuretic      CYP3A4 induction (Eap et al. 2002).

St. John's wort (Hypericum perforatum) - Ingredient in various OTC products.  Herb used as antidepressant.  Induces CYP3A4; 47% decrease in methadone (Eich-Hochli et al. 2003; Scot and Elmer 2002).

Tobacco - various brands     Habitual smoking.  ( some mixed reports, but most indicate reduced effectiveness of methadone (Moolchan et al. 2001; Tacke et al. 2001)

Urinary Acidifiers (Ascorbic Acid) -  Vitamin C (large doses); K-Phos     Dietary supplement; keeps calcium soluble.     Methadone is excreted by kidneys more rapidly at a lower pH (Nillson et al.1982; Strang 1999)..

May result in altered metabolism or 
unpredictable interactions in com-
bination with methadone.
           

Didanosine (ddl, buffered tablet) -  Videx®     NRTI antiretroviral     Decrease in ddl concentration (Rainey et al. 2000) Effect not seen with enteric-coated ddl (Faragon and Pillero 2003; Friedland et al. 2002).

Dextromethorphan - Robitussin®, Vicks® Delsym®, Touro Dm®  Cough Medicine Increased levels /effects of dextromethorphan proposed (Levy et al. 2000).

Interferon-alfa+ribavirin - Rebetron® (possibly also pegylated interferon, Pegasys®) Antihepatitis C treatment     Side effects can mimic opioid withdrawal symptoms and methadose is often increased (Schafer 2001; Sylvestre 2002).

Nifedipine - Procardia®, Adalat®     Cardiac medication (Ca-channel blocker)     Possible increase in nifedipine proposed (Levy et al. 2000; Strang 1999) 

Stavudine (d4T)  - Zerit®     NRTI antiretroviral      Decrease in d4T concentration; no effect on methadone (Rainey et al. 2000).

Zidovudine (AZT) - Retrovir ®, AZT combinations, (Combivir®, Trizivir®)     NRTI antiretoviral     AZT concentration increased 40% with methadone; more frequent AZT side effects are possible (McCance-Kantz et al. 1998).


The opioids will be classified as: (1)  Agonists (2) Antagonists  (3) Mixed- Agonists - Antagonists.

 Experimental studies involving the binding of opioid compunds to specific areas in the central nervous system and peripheral tissues have substantiated the hypothesis that stereospecific opioid receptors exist which medicate the actions of the drugs. These receptors also appear to be the site of action of the endogenous opioid-like substances and have been divided into three major categories, designated µ (mu),  k (kappa),  and  ò (delta); it has also been proposed that at least two subtypes of each category  of opioid receptors exist.  Experimental evidence suggests  that activation of µ receptors ( found principally at supraspinal sites) is associated with analgesia, respiratory depression, euphoria, and physical dependence; thereceptors (located within the spinal cord) are believed to mediate spinal analgesia, miosis, and sedation.  The Ó receptors may influence affective behavior, and although some believe that activation of these receptors plays a role in opioid-induced analgesia, this remains controversial.

A few years ago the existence of a fourth opioid receptor was postulated, the ó (sigma) receptor. The binding of certain opioids to these "receptors" (now called sigma sites) has been associated with dysphoria, psychotomimetic effects and respiratory stimulation.  Sigma sites are not considered true opioid receptors since a number of different compounds, like antipsychotics, certain antihistamines, some steroids and phencyclidine, none of which are opioid in structure, have binding affinity for these sites.

Agonistic opioids act as analgesics by binding to and activating both mu and kappa receptors in the brain and spinal cord.  The agonist opioid drugs  have both affinity for these receptors  and efficacy (the ability to stimulate the receptors and to produce an effect) and, therefore, mimic the activity of the endogenous opioid peptides.

Chemically, the opioid agonists include a number of structurally different classes of drugs, all of which have pharmacologic effects similiar to those of morphine. These in-clude the phenanthrene derivatives, which encompass both the naturally-occurring alkaloids of opium, (e.g., morphine and codeine), and their semi-synthetic deriatives, (e.g., hydro-morphone, oxycodone, and oxymorphone), a morphinan derivative (levor-phanol), phenylpiperidine derivatives (alfentanil, fentanyl, meperidine and sufentanil) and diphenylheptane derivatives (methadone and propoxyphene).  Although morphine is the oldest drug of this class, it remains as the prototype for the group and the standard to which all other opioid analgesic opioids are compared.

Opioids-Analgesics-Common 450 pathways with
methadone; additive effects possible. Long-acting excitatory metabolites of meperidine and pro-poxyphene 
can reach  toxic levels (Harrington  
et al.
1999).                                                                                         
Warning:  Use opioids with extreme care with alcohol, sedatives, anti-anxiety, and other medications and with your physician's supervision  Dangerous when mixed! 

                                                                                                                        Alfentanil  - Alfenta®                          Hydrocodone - Vicodin®

Sublimaze-Fentanyl®                           Meperidine - Demerol®

Morphine-Duramorph®, MS Contin®     Oxycodone -  Oxycontin®

Propoxyphene - Darvon®                 

Opioid Antagonists displaces methadone 
causing severe withdrawal !!!!

The opioid antagonists bind to all three categories of opioid receptor sites throughout the body, but fail to activate them. These compounds are not used for analgesia; rather, the therapeutic utility of these drugs lies in their ability to reverse the adverse effects associated with an overdose of an agonist opioid or to prevent the effects of opioids in individuals who abuse these drugs. 

Opioid antagonists are contraindicated with methadone. The medications below may precipitate opioid withdrawal. They are used for treatment of alcoholism, or blockade or reversal of opioid effects.   Interaction displaces methadone on  µ-opioid receptors causing severe withdrawal.      

Naltrexone - Revia® , Depade®                             Naloxone - Narcan®     

Nalmefene - Revex®

The compounds that comprise the mixed agonist-antagonist group are more recent additions to the clinically important opioids.   These drugs are semi-synthetic deriatives of morphine, the chemical structures  of which have (1) agonistic activity at some k  re-ceptors but antagonistic activity at µ receptors , e.g., pentazocine, butorphanol, and nalbuphine, or (2) partial agonistic activity at µ receptors and antagonistic activity at the k receptors, e.g., buprenorphine.  All are effective analgesics since they stim-ulate either µ or k receptors.

Buprenorphine - Buprenex®, Subutex®, Suboxone®   Butorphanol - Stadol®

Dezocine - Dalgan®     Nalbuphine - Nubain®       Pentazocine - Talwin®

The medications listed above as mixed-agonist-antagonist group can displace methadone on  µ-opioid receptors to cause withdrawal (DeMaria 203; Kalvik et al. 1996)

Tramadol - Ultram®       Synthetic Analgesic    Potentially may cause withdrawal in persons already taking opioids (Ultram Pl 1998).                                       

The drugs above may not be all inclusive of drugs/brands that might be contraindicated or interact with methadone.

Reference:  Methadone Treatment For Opioid Dependence   Edited by:   Eric C. Strain; Maxine L. Stitzer; 1999 The John Hopkins University Press                   

Reference:  The Pharmacology Of Drug Interactions            Edited by:  Patricia K. Anthony   2000 CopyRight      

Reference:  Handbook Of Pain Management    Third Edition  G. John Digregorio; Edward J. Barbieri; John F. Camp; Maurice F. Prout; Gerald H. Sterling   1991

Reference:  AT Forum  Methadone - Drug Interactions      (Medications, Illicit Drugs  & Other Substances) Stewart B. Leavitt, PhD; Editor, AT Forum  

 If you would like a list of the medications that interact with methadone in booklet form, I recommend you go the Url address below :

   Click Here                                         http://www.atforum.com

Click on "Addiction Resources" after you arrive at the url address, then look for Addiction Treatment Forum  Methadone - Drug Interactions   (Alphabetical Listing by Generic & Brand Names).  Therefore, you have an updated pamphlet that you can just glance at to check, because in all honesty, there are few physicians that are up to date on reactions with methadone and you may discover that even your own pharmacist is not aware of all of them. Check it out - I think you will like what you see and you can print it out and keep a copy with you at all times.

Updated:  5 January 2005 

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