Showing posts with label opiate addiction. Show all posts
Showing posts with label opiate addiction. Show all posts

Sunday, October 17, 2010

Codeine Blues: End of the Line for an Opiate with Issues


Canada, UK consider phasing out the drug.

Among the many memorable anecdotes that have been uttered at the opening of an AA or NA meeting, surely one of the great ones is this: “I’m an addict, and a heroin junky. I went to the dentist today, and he sent me home with a prescription for Tylenol 3. And I thought: Do I really want to endanger my sobriety over a shitty buzz like codeine?”

Canada and the United Kingdom are ready to phase it out entirely. The U.S. Food and Drug Administration (FDA) issued a warning about it for nursing mothers as far back as 2007. Codeine, widely popular for its low euphoriant effects, and subsequent (if theoretical) decreased potential for abuse, may not be as strong as morphine and dilaudid, but it is perhaps the most commonly prescribed opiate in the world—and it comes with a major flaw. Unlike other opiates, codeine is very unpredictable in its interactions with an enzyme called CYP2D6. This enzyme is a primary workhorse in the body’s process of breaking down and excreting many different drugs. Poor metabolizers produce less of this crucial enzyme, which means that drugs are broken down and excreted at a much slower pace (See my earlier post ).

 Specifically, as two physicians recently wrote in the Canadian Medical Association Journal (PDF),
“polymorphisms occur in the cytochrome P450 isoenzyme CYP2D6 that enhance codeine metabolism to morphine.” In 2007, following the death of an infant nursed by a codeine-using mother, the FDA “warned nursing mothers that if they took codeine after childbirth, their newborns might be at risk for a morphine overdose,” according to a New York Times report.

Alternatively, other metabolizers may have little or no reaction to codeine-based medications. Drugs of abuse severely complicate these enzymatic issues, since addicts and alcoholics are not known for volunteering information about their condition to medical or hospital personnel.

Testing for the enzyme is possible, but not likely to catch on with cash-strapped medical and dental centers. Dr. Noni MacDonald at the University of Halifax and Dr. Stuart MacLeod at the University of British Columbia argue in the CMAJ that these genetic variations “can have potentially serious clinical consequences. The wrong combination can result in toxic levels of morphine, even at conventional doses of codeine.” The younger the user, the more susceptible he or she will be to these effects, “possibly because of age-related maturation differences in the blood-brain barrier.” The authors warned that serious side effects “including life-threatening respiratory depression,” have also been reported in adults.

The ultrafast metabolizing variant of CYP2D6 is not evenly distributed throughout the world’s population. The number of people in danger of experiencing high morphine levels after codeine use range from 40% in North Africa to 3% in Europe, the authors say. Rates in the U.S. are 8%, meaning roughly one in ten Americans risk an adverse reaction when taking codeine.

Since the groups at highest risk are infants and children, nations have taken various steps to mitigate the risk. “Switzerland sets the minimum age for codeine-based treatment at 1- years, the Netherlands at 1 year, the United States at 3 years and Canada at 2 years.”

Despite these controls, the authors strongly argue for “a more direct approach,” calling for doctors to “stop using the prodrug codeine altogether and instead use its active metabolite, morphine. Not only is the metabolism of morphine more predictable that that of codeine, but also it’s cheaper.” So codeine is just not consistently good at what it does. Problem is, an opiate doesn’t have to be good to be great, as innumerable codeine addicts can attest.

The argument in Canada made sense to Britain’s watchdog agency for medicines, the Medicines and Healthcare products Regulatory Agency (MHRA). According to a report in The Independent by science editor Steve Connor, the MHRA “wrote to medical authorities in the UK warning that its experts have advised that all over-the-counter liquid cough medicines containing codeine should no longer be used in children under the age of 18,” and that “the risks of [over-the-counter] cough medicines for children containing codeine outweigh the possible benefits.”

Codeine is typically offered in paired form, with either acetaminophen or aspirin, as protection against opiate abuse. In theory, a drug abuser would be likely to trigger a Tylenol overdose before reaching an opiate overdose on codeine pills. However, it is perfectly possible to maintain an active opiate addiction on prescription Tylenol 3s, Fiorinal, or Phenergan cough syrup, among other drugs.

And finally, I would not be revealing any great secrets by suggesting that the extraction of codeine from a codeine-acetaminophen tablet through basic solubility and filtration procedures may not be something one needs to be a chemistry major to pull off. 

The OTC medicine industry in the UK views all of this as a tired argument. A spokesperson for Britain’s Proprietary Association, which represents over-the-counter manufacturers, said: "There has already been a long-drawn-out discussion of codeine. If its value as a pain reliever had not outweighed the risks then it would have been withdrawn and the point is that codeine still has a value as a pain reliever.”


Sunday, February 21, 2010

Of Mice and Methamphetamine


Diabetes drug being tested for addiction.

It’s a mouthful: peroxisome proliferator activated receptor gamma (PPAR-gamma). 

Peroxisomes are specialized subunits inside cells that help metabolize various substances, including fatty acids and certain toxins. A blockbuster member of this drug family—Avandia—is a much disputed but immensely lucrative diabetes medicine that may cause heart failure.

(Partial Agonist Ppar Gamma Cocrystal)--------->

PPAR gamma agonists belong to a class of drugs known as thiazolidinediones. Clinical research has pointed toward additional therapeutic applications for thiazolidinediones in the areas of inflammation and cancer. The only approved use for thiazolidinediones is in the treatment of diabetes, but the drug class has also been studied for treatment of polycystic ovary syndrome, psoriasis, autism—and now drug addictions. A PPAR compound will soon undergo testing under the auspices of the Omeros Corporation, with funding from the National Institute on Drug Abuse (NIDA).

Omeros says it has developed a novel drug “for the prevention and treatment of addiction to substances of abuse, such as opioids nicotine and alcohol, as well as other compulsive behaviors, including eating disorders.” Phase 2 clinical studies on opiate addiction by Dr. Sandra D. Comer and associates at the New York State Psychiatric Institute will begin soon, according to an Omeros press release.

Such claims add up to a tall order for any anti-craving drug. In fact, no drug currently exists for the treatment of so wide a spectrum of addictive disorders. Nonetheless, Omeros claims to have demonstrated a previously unknown link between a variant of this family of diabetes medications and addiction.

The heart problems linked to the PPAR marketed as Avandia may be a special case. According to an article by Gardiner Harris in the New York Times, based on government reports obtained by the newspaper: “If every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart. Avandia, intended to treat Type 2 diabetes, is known as rosiglitazone and was linked to 304 deaths during the third quarter of 2009.” Actos, another thiazolidinedione, has not been linked to any heart trouble.

 GlaxoSmithKline is disputing the findings. A number of other pharmaceutical houses—AstraZeneca, and Eli Lilly among them—discontinued their first generation PPAR drugs. The derivative marketed as Avandia is not the compound under study by Omeros.

There is little clinical evidence to bolster the PPAR theory. A recent Spanish study suggested the possibility that PPAR gene variants may be associated with higher alcohol consumption in a small sampling of Mediterranean drinkers.

ResearchBlogging.orgThe most comprehensive study may be a 2007 paper in Neuropsychopharmacology by Takehiko and coworkers, demonstrating that PPARs can have an effect on behavioral sensitization to methamphetamine in mice.

Behavioral sensitization is the name for the progressive increase in meth-driven locomotor activity over time. The researchers found that a PPAR variant “plays an inhibitory role in the expression” of sensitization to methamphetamine. The action takes place in the brain’s nucleus accumbens, where repeated hits of meth cause an increase in PPAR expression, according to the researchers: “These results indicate that [an isotope of PPAR] in the reward system is involved in behavioral sensitization to METH.”

What is the mechanism of action? The researchers speculate that upregulation and activation of PPAR in the meth-crazy mice may be due in part to an inflammatory response. PPAR, in theory, exerts anti-inflammatory activity in brain cells.  And psychostimulants, according to the researchers, “upregulate the expression of target genes via activation of inflammatory-responsive transcriptional factors.”

Maeda, T., Kiguchi, N., Fukazawa, Y., Yamamoto, A., Ozaki, M., & Kishioka, S. (2006). Peroxisome Proliferator-Activated Receptor Gamma Activation Relieves Expression of Behavioral Sensitization to Methamphetamine in Mice Neuropsychopharmacology, 32 (5), 1133-1140 DOI: 10.1038/sj.npp.1301213

Tuesday, May 5, 2009

Acupuncture for Addiction: It Doesn't Look Good


Needles fail in latest study of opiate detox.

Acupuncture as a treatment for drug addiction took another punch recently in a study published in the Journal of Substance Abuse Treatment. In “Auricular acupuncture as an adjunct to opiate detoxification treatment,” the study authors investigated whether acupuncture would “add value” to a standard methadone-based detoxification process. For the two-week study, 82 opiate-addicted patients were randomly assigned to either ear acupuncture by qualified acupuncturists, or the attachment of ear clips by non-professionals. Each day, the study participants were tested for withdrawal severity and craving.

"On none of the 14 days,” the authors report, “were there statistically significant differences between patients allocated to ‘real’ acupuncture and the ‘sham’ treatment. Such statistically insignificant difference as there were favored the ‘sham’ treatment....”

The results, say the authors, “are consistent with the findings of other studies which failed to find any effect of acupuncture in the treatment of drug dependence.” Moreover, the authors conclude, this finding is “particularly disappointing as if anything the circumstances favored the acupuncture option,” since in contrast “the alternative may not have been seen as a convincing therapy.” Nevertheless, “like the featured study, previous studies of acupuncture in the treatment of opiate addiction have been unconvincing.... The ‘ineffective’ verdict on acupuncture extends to the treatment of cocaine dependence,” the authors maintain, while an attempt to replicate earlier positive findings on acupuncture for alcohol dependence found no benefits, either.

The authors also reflect on whether such offerings, though of dubious value, attract addicts to treatment centers. “The possibility remains that offering something concrete like acupuncture helps attract people to services, and that doing something both clients and staff believe is worthwhile (even if it is a ‘sham’ procedure) helps retain patients in treatment, and in doing so improves outcomes.”

Of course, this is only one study out of many, and acupuncture enthusiasts remain as optimistic as ever. Proponents of acupuncture treatment continue to petition the National Institute on Drug Abuse (NIDA) for endorsement. Most reports of success remain anecdotal. Nonetheless, the National Acupuncture Detoxification Association estimates that there are currently 200 acupuncture detoxification programs operating in the United States and Europe.


Photo Credit: The 217

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