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Significant drug interaction between Ciprofloxacin and Methadone.

There is a significant drug interaction between Ciprofloxacin and Methadone.  Cipro may inhibit cytochrome P450 3A4 up to 65%.   Since this is the primary  enzyme responsible for metabolizing methadone, Cipro may elevate methadone  levels significantly.  That this can cause a clinical opioid overdose is demonstrated  in the attached article, which I have also appended to the end of this email, for those  of you who can open neither Acrobat (PDF) nor Wordperfect files.  This is potentially  significant and serious for an unknown (but certainly non-zero) proportion of  Methadone patients.  Because of the stigma of methadone treatment, patients often do  not share information about their methadone use with health care providers (other than  clinicians involved in their OAT).  Many Americans are, or soon will be, taking Ciprofloxacin to prevent potentially lethal pulmonary anthrax.  Methadone patients who  do this may need to lower their dose of methadone to prevent potentially dangerous  overdose.  Information about this interaction needs to go out ASAP to the  medical community in general, and to OAT providers and patients in particular.

I have already contacted the JAMA medical news staff, who would be glad to  include this information in the next available news from health agencies column,  but that will not be until the November 21 issue.  I have also contacted Mark  Parrino.  I believe that we need to put out a press release/advisory  ASAP and  especially target the media in the DC area, New York, New Jersey, Florida  and the Postal Workers union, as well as the methadone patient advocates and  public health officials.   This does not mean that methadone patients cannot take  Cipro.  It merely means that their methadone dose may need adjustment and that  they and their medical providers need to be informed of this.  It is unclear what  effect Cipro might have on LAAM kinetic, possibly an acute lowering of NorLAAM  and DinorLAAM levels, with a consequent, but short lived, withdrawal syndrome.  Patients on LAAM who start Cipro should probably have Extra EKG's to be sure  that the QT interval does not rise above 480 msec during the acute changes, until  the new levels stabilize.

Any thoughts you have on these bio-medical issues or how to get the word out  will be much appreciated, sincerely, 

Alan Trachtenberg, MD, MPH, Adjunct Associate Professor,
George Washington University Medical Center, and Uniformed Services University of the Health Sciences (USUHS), and Medical Director, Office of Pharmacologic and Alternative Therapies (OPAT),  Center for Substance Abuse Treatment (CSAT),  Substance Abuse & Mental Health Services Administration (SAMHSA),  United States Public Health Service (USPHS) atrachte@samhsa.gov   OR  voice: 301-443-1281   fax: 301-480-7505  cell:301-792-3980
official homepage:  http://www.opat.samhsa.gov

Methadone, ciprofloxacin, and adverse drug reactions Karin Herrl,n, M~rta Segerdahi, Lars L Gustafsson, Eija Kalso Lancet  356:2069-70. 12/16/2000 Research Letters.

Ciprofloxacin, given to a patient successfully treated with methadone for more  than 6 years, caused profound sedation, confusion, and respiratory depression.  We suggest that this was caused by ciprofloxacin inhibition of CYPIA2 and CYP3A4  activity, two of the cytochrome p450 isozymes Invoived in the metaboilsm of  methadone.

A 42-year-old woman in pain because of Ogilvie s syndrome (chronic intestinal  pseudo-obstruction) was managed successfully with oral methadone 140 mg/day  for more than 6 years (panel). She was admitted to an internal medicine ward  because of urosepsis. 2 days after introduction of oral ciprofloxacin (750 mg twice  daily) the patient became sedated and confused, and required an extended  hospital stay. Ciprofloxacin was replaced by co-trimoxazole and the patient  recovered within 48 h. Later, ciprofloxacin was reintroduced three times in  three different departments because of relapsing urinary-tract infections, and  the patient became sedated on all occasions. On the last occasion the patient  developed heavy sedation and respiratory depression, but immediately became  alert with increased respiratory frequency when given naloxone (04 mg) intramuscularly. On each occasion, after discontinuation of ciprofloxacin,  the patient regained her normal alertness. On the second and third occasions  the patient had the same concurrent medication as at the first occasion, however  on the fourth occasion venlafaxine had been replaced by fluoxetine (panel). 

The terminal half-life of methadone is about 30 h with a wide range. Adverse  effects are similar to other opioids. The most serious adverse effect of  methadone is respiratory depression. Low concentrations mainly reduce  respiratory rate whereas higher doses also diminish tidal volume. The  metabolites of methadone are not considered to be pharmacologically active. 

Recent studies indicate that the cytochrome p450 isozymes CYP1A2, CYP2D6, and  CYP3A42 are involved in methadone metabolism. Methadone concentrations were  reported to have increased in 13 addicts after initiation of fluvoxamine and  fluoxetine, respectively. Fluvoxamine is a strong inhibitor of CYP1A2 and  fluoxetine is a strong inhibitor of CYP2D6; the interaction would indicate that  methadone is metabolised by both GYP 1A2 and CYP2D6.  Ciprofloxacin is a quinolone antibiotic and a potent competitive inhibitor of  CYP1A2. Ciprofloxacin is metabolised to 55¯75% and partly excreted, unchanged  in the urine. The inhibitory potency of ciprofloxacin was determined by calculating  the decrease in GYP 1A2 activity after addition of ciprofloxacin into a medium  for human liver microsomes, which caused a 70% reduction in the GYP 1A2-mediated  demethylation rate of caffeine in vitro.3 Furthermore, the activity of CYP3A4  was depressed by 65% in human hepatic microsomes by ciprofloxacin.4  Thus, there are two common enzymes for ciprofloxacin and methadone which implies a potential for a pharmacokinetic drug interaction. In addition to the suspected pharmacokinetic interaction, contributing factors have to be considered. 

The patient was a smoker with, presumably, an induced CYP1A2 enzyme  capacity that may have counted for a larger part of methadone metabolism  than in non-smokers. Thus, the inhibition of CYP1A2 by ciprofloxacin may have had  a greater impact in this patient than in non-smokers. During the suspected  interaction the patient also had an infection (panel). 

Theoretically, increased methadone concentrations due to inhibition of CYPIA2  and CYP3A4, may be more pronounced in patients who are poor metabolisers  via CYP2D6, but this patient was a normal extensive metaboliser. However, she  was on venlafaxine which is a moderate CYP2D6 inhibitor. Interestingly, at the last  occasion venlafaxine had been replaced by fluoxetine which is a stronger  inhibitor of CYP2D6 than venlafaxine, and the adverse opioid effect was more  severe compared with the first three occasions.  

Naloxone reversal of the respiratory depression strongly suggests that the  respiratory depression was caused by methadone. It is probable that  ciprofloxacin caused raised concentrations of methadone through enzyme  inhibition. The patient was given the drug combination four times, thus,  there were three positive rechallenges. This illustrates that even if the patient  has been informed about a drug interaction, the drug could be re-administered  if the patient is admitted to a different department. Furthermore, this case  illustrates that long-term use of methadone does not protect from overdosing  due to interaction. According to a scale developed to estimate the probability  of adverse drug reactions; this case was assessed as a definite drug interaction.

An interaction between methadone and ciprofloxacin has not been reported  previously. Both methadone and ciprofloxacin are already in widespread clinical  use and with the increasing consumption of methadone, both in maintenance  programmes for drug addicts and as an analgesic for both cancer and  non-malignant chronic pain, patients treated with methadone will be encountered  in family practice as well as in several other specialties.

This pharmacokinetic drug interaction needs further clinical investigation,  including the measurement of serum methadone enantiomers, because methadone  metabolism is suggested to be stereoselective. We suggest that clinicians are  more aware when methadone and ciprofloxacin are given concomitantly and that  both clinicians and patients should be given more information about potentially  dangerous interactions between methadone and other drugs. 

We thank Eva Gothason and Aqueta Heller at the Division of Pain  Management, for their cooperation and data collection. This work was  supported by grants from the Swedish Medical Research Council (3902) and  the Swedish Cancer Fund (3948). 

 I       Eap CB, Bertschy G, Powell K, Baumann P. Fluvoxamine and
         fluoxetine do not interact in the same way with the metabolism of
         the enantiomers of methadone. J Clin Psychophannacol 1997; 17:
         113¯17.
 2       Iribarne C, Dreano Y, Bardou LG, Menez IF, Berthou F.
         Interaction of methadone with substrates of human hepatic
         cytochrome P450 3A4. Toxicology 1997;    117: 13¯23.
 3       Fuhr U, Anders E-M, Mahr G, Sorgel F, Staib AH. Inhibitory
         potency of quinolone antibacterial agents against cytochrome
         P4501A2 activity in vivo and in vitro. Anrinzign,b AgcutN Chenithe,
         1992; 36: 942¯48.
 4       McLellan RA, Drobitch RK, Monshouwer M, Renton KW.
         Fluoroquinolone antibiotics inhibit cytochrome P450-mediated
         microsomal drug metabolism in rat and human. Drug Metab Dispos
         1996; 24: 1134¯38.
 5       Naranjo CA, Busto U, Sellers EM, er al. A method for estimating
         the probability of adverse drug reactions. Cli,, Pharmacol Ther 1981;
         3O~ 239-45.

Division of Clinical Pharmacology at the Department of  Medical Laboratory Sciences and Technoiogy (K Herrlin MO,  L L Gustafsson MD), and the Division of Pain Management  at the Department of Anaesthesia and intensive Care  (M Segerdahi MO, E Kalso Mo), Karoiinska institutet at Huddinge  University Hospltai, Huddinge, Sweden 

Correspondence to: Dr Karin Herrlin. Division of Clinical Pharmacology, Huddinge Univers~tV Nosp~tal. S-141 86 Nuddrnge,  Sweden  (e-mail: Karin.Herrlhn@Iabtek.ki.se) 

Clinical data including drug history for a patient at the time of a suspected  drug interaction (first exposure) between methadone and ciprofioxacin causing  heavy sedation, confusion, and respiratory depression Medical hlstoiy Ogilvie*s syndrome (pseudo-obstruction)  Dose and route of administration of methadone   Methadone (mixture 140 mg)  since 6 years  Dose and route of administration of ciprofioxacin       

Ciprofloxacin (tablet  750 mg) since 2 days indication for ciprofioxacin treatment  Urosepsis  Continuous concurrent medication and main route of elimination  Metabolised at least partly by CYP1A2   None  Metabolised at least partly by CYP2C19  Omeprazole (tablet, 20 mg twice daily) 

Metabolised at least partly by CYP2D6   Venlafaxine (tablet, 75 mg twice daily)*  Metabolised at least partly by CYP3A4   Runitrazepam (tablet, I. mg)
         Metronidazole (tablet, 400 mg twice daily)t
         Nitrazepam (tablet, 5 mg when needed to a maximum of
         four tablets/day)
 Other routes of elimination     Cyclizine (tablet, 50 mg)
         Furosemide (tablet, 40 mg)
         Paracetamol (tablet, 500 mg when needed to a maximum of
         eight tablets/day)
         Propantheline bromide (seven 15 mg tablets/day)
 Smoking Yes
 Kidney function (as measured by serum creatinine)       Normal
 Uver function (as measured by ALT, albumin, and iNR)    Normal
 *Venlafaxine was replaced by fluoxetine at the time of the fourth exposure
 to ciprofloxacin. t=Continuous prophylaxis at the time of the first exposure.

 Metronidazole was then discontinued and not given at the time of the last
 three exposures. INR=lntemational normalised ratio.  ALT=alanlne transferase.