gtreiow

作者：Nancy A. Melville  
出處：WebMD醫學新聞

　　December 17, 2009 (加州洛杉磯) — 根據發表於美國成癮精神科學會第20屆年會與研討會的新研究，細胞色素P450 (cytochrome P450)上的基因異常會使病患加速鴉片類藥物的代謝，使得需要以更高劑量來控制疼痛。
　　
　　慢性疼痛病患需要更高劑量的鴉片類藥物時，醫師會擔心他們可能成癮或濫用，但是，本研究的第一作者、加州Veract 難治型疼痛門診的Forest Tennant醫師表示，可能有其他因素影響。
　　
　　Tennant醫師表示，長久以來，我認為某些人可能是因為基因代謝異常，而使他們需要非常高的或不尋常的疼痛控制處方。
　　
　　一般認為，這些人一定是藥物成癮或濫用，但是有些人認為，或許還有其他原因。這些病患有相當多並沒有濫用史；他們甚至不抽菸，也不是藥物成癮者。
　　
　　為了評估此一議題，Tennant醫師招募15個每天需要相當於1000mg以上嗎啡的慢性疼痛病患，且檢測細胞色素P450 2C9或2D6這兩種基因型或檢測其中一種。給予這些人一般鴉片類藥物劑量之後1小時，檢測他們的血清鴉片類藥物濃度。
　　
　　【懶惰的基因？】
　　結果顯示，細胞色素P450基因型異常的3個人，在給藥後只有達到1-2小時的疼痛緩解，檢測2C9基因型的8個人中，有2個是不佳代謝者，這兩人在給藥後1小時的血清fentanyl濃度都很高(8.1與16.4 ng/mL)。2D6基因型的病患中有1個是不佳代謝者，在給藥後1小時，血清中測不到oxycodone與其代謝物oxymorphone。
　　
　　Tennant醫師表示，雖然相當初步，這個結果提供了一些證據，至少有一些高劑量止痛藥病患為細胞色素P450基因型異常。
　　
　　他表示，大約有50種已知的細胞色素基因異常，目前我們只能檢測其中3到4種。但是，我們現在做的這些檢測，結果認為這些病患有一些代謝因素需被納入考量，可以解釋這些病患何以需要高於一般用藥劑量的異常劑量。
　　
　　Tennant醫師指出，他猜測這種異常包含一種「懶惰基因」，造成需要較高藥物劑量的反應。
　　
　　他表示，我們相信，必須靠這麼高的藥物濃度才能讓懶惰基因運作－你多少得有點力量來餵它。在其他藥物學領域中有這種情況，例如薄血藥，你必須有很高的劑量來讓有缺陷的基因運作。
　　
　　雖然該研究依舊處於早期階段，但此類異常的基因檢測將可以幫助醫師確認與更有效地治療這些病患。
　　
　　【可能的篩檢工具】
　　將可以幫助醫師更確定哪些病患更容易有風險成為鴉片類藥物依賴者。
　　
　　Tennant醫師指出，這是必然的— 高劑量引起依賴性。我不知道它是否足以讓人走上街頭變成毒癮者，但是，甚至只是為了獲得小量的止痛，都可能需要相當依賴高劑量、持續日以繼夜的給藥。
　　
　　此發現也提出這些基因因素是否會促使其他物質濫用，包括酒精。他表示，至少有1個研究對象加深此一疑慮。
　　
　　5個2C9基因型者中有1人指出，曾經是酒癮者，而且，她表示，「很好笑，我外出和朋友飲酒，每個人都喝醉了，我還是好端端的。」
　　
　　Tennant醫師指出，他繼續檢測另外25個研究對象，發現約有20%高劑量病患有這些基因異常。他認為，既然現在有一些基因檢測已經上市，醫師們或許會考慮進行這些基因型檢測。
　　
　　他表示，18個月前，我無法進行此研究，因為沒有這種檢測工具，但是我認為，每個服用鴉片類止痛藥物的病患現在都必須檢測。不只是增加研究資料，還可以提供重要資訊給保險公司和其他給付這些藥物者。
　　
　　他們需知道發生何事，知道這些人為何服用較高劑量，他們可能會懷疑這些病患是否為成癮者。
　　
　　【爭議的領域】
　　隨著止痛藥成癮越普遍，懷疑某些案例是成癮者也不無道理，不過，夏威夷大學精神科教授Jon Streltzer醫師表示，他質疑某些病患「需要」高劑量鴉片類藥物來治療慢性疼痛的假設。
　　
　　國際身心醫學院理事長Streltzer醫師表示，這是一個有爭論的觀念，在細胞學、生理學和臨床方面有不少證據反駁它，也許是病患對高劑量鴉片類藥物依賴性有不同的感受性。
　　
　　他認為，這不表示基因因素無關，它們可能是解決這多元謎題的一環。
　　
　　Streltzer醫師向Medscape Psychiatry表示，長久以來，都相信基因因素和鴉片類成癮性有關，只是還不清楚是哪些基因以及怎樣的機轉。
　　
　　此外，長期服用鴉片類藥物也會使腦部本身有所改變，改變的細胞的反應方式，這被視為與渴望有關，對於慢性疼痛病患來說，會感到疼痛而需要更多止痛藥物。
　　
　　事實上，病患對疼痛更敏感 —止痛藥本身造成。Streltzer醫師表示，許多報告指出，藉由多種部份相同的機轉，造成長期服用鴉片類藥物者的疼痛敏感性。減緩鴉片類藥物依賴計畫中的病患指出，他們的疼痛有所改善。
　　
　　不過，Tennant醫師指出，病患說他們需要高劑量時，醫師不應排除基因異常等可能性。
　　
　　Tennant醫師表示，底線是，當病患對我們抱怨嚴重疼痛且需要相當高劑量時，我們不能驟下結論認為是濫用。可能是必須納入考量的代謝因素可以用來解釋這些病患何以需要特高量的處方。
　　
　　Tennan醫師和 Streltzer醫師皆宣告沒有相關財務關係。
　　
　　美國成癮精神科學會(AAAP)第20屆年會與研討會：壁報5。發表於2009年12月4日。


Cytochrome P450 Gene Implicated in Need for High-Dose Pain Medication

By Nancy A. Melville
Medscape Medical News

December 17, 2009 (Los Angeles, California) — Genetic abnormalities in cytochrome P450 may cause some patients to metabolize opioids at an accelerated or retarded rate, prompting the need for higher doses of medication to control pain, according to a new research presented here at the American Academy of Addiction Psychiatry 20th Annual Meeting Symposium.

Chronic pain patients who require high doses of opioids may lead clinicians to suspect them as possible addicts or abusers, but Forest Tennant, MD, lead author of the study and a physician with the Veract Intractable Pain Clinic in West Covina, California, said other factors are at play.

"I have long felt, as have others, that there could be genetic metabolic abnormalities in some people who require very high or unusual regimens to control pain," Dr. Tennant said.

"The general idea has been that these people must be drug addicts and abusers, but some felt there was perhaps something behind all of this. A lot of these patients have no history of abuse; they don’t even smoke cigarettes and just don’t fit the profile of drug addict."

To evaluate the issue, Dr. Tennant recruited 15 chronic pain patients who required 1000 mg or more of a morphine equivalent per day and who tested for deficiencies in one or both of the cytochrome P450 2C9 or 2D6 genotypes. The subjects’ opioid serum concentrations were determined about 1 hour after administration of their usual opioid dose.

Lazy Gene?

The results showed that all 3 patients with cytochrome P450 genotype abnormalities achieved only 1 to 2 hours of pain relief after receiving the medication. Two of 8 patients who tested for the 2C9 genotype were poor metabolizers, with both showing very high serum concentrations of fentanyl (8.1 and 16.4 ng/mL) 1 hour after dosing. One of the patients with the 2D6 genotype was also a poor metabolizer and had no detectable serum concentrations of oxycodone and its metabolite, oxymorphone, 1 hour after dosing.

The findings offer some evidence, albeit highly preliminary, of genetic cytochrome P450 abnormalities in at least some high-dose pain medicine patients, Dr. Tennant said.

"There are about 50 known genetic abnormalities of the cytochromes, and we can only test 3 or 4 of these at this time," he said. "But even with the tests we did here, the results suggest that there may be metabolic factors with these patients that need to be taken into consideration and may explain why these patients need odd [medication] regimens [requiring dosages that are higher than normal]," he said.

Dr. Tennant added that he suspects that the abnormalities involve a "lazy gene" that only responds to higher doses of a medication.

"We believe those very high blood levels of the drug may be necessary to make the lazy gene work — you need to sort of force feed it," he said. "This has been seen in other areas of pharmacology, such as blood thinners. You have to get a very high dose to make the defective gene work."

Although the research is still in its early stages, genetic testing for such abnormalities may have the potential to help clinicians identify and more effectively treat this patient population.

Possible Screening Tool

It may also help clinicians better detect which patients may be at a greater risk of becoming opioid dependent.

"That’s the corollary to this — high doses could cause dependence," Dr. Tennant noted. "I don’t know if it could be enough to cause people to go to the street and become addicts, but in order to get even a modicum of pain control, they may be extremely dependent on taking high doses on a regular, round-the-clock basis."

The findings also raise the question of whether these genetic factors could prompt abuse of other substances, including alcohol. At least one of the study subjects fueled that suspicion, he said.

"One of the 5 with the 2C9 genotype did report being an alcoholic at one point, and she said ‘It’s funny, I would go out and drink with friends and everyone would be getting drunk and nothing would be happening to me’."

Dr. Tennant noted he has subsequently tested 25 additional subjects and found that about 20% of high-dose patients had these genetic abnormalities. He suggested that now that these genetic tests are available commercially, physicians may want to consider testing for these genotypes.

"Eighteen months ago, I wouldn’t have been able to do this research because the test wasn’t available, but I feel every patient who is taking opioids for some pain should now be tested," he said. "Not just to add to a database but to give essential information to insurance companies and any other parties who are paying for the drugs."

"They need to know what’s going on, why these people are taking higher doses of drugs, and they likely wonder whether these patients are addicts."

Controversial Area

With pain medication addiction widespread, the temptation to suspect addiction in many cases only makes sense however, and Jon Streltzer, MD, a professor of psychiatry at the University of Hawaii, Manoa, said he questions the very assumption that some patients "require" high-dose opioids to treat chronic pain.

That is a controversial concept that has much evidence against it at the cellular, physiological, and clinical levels. It may be instead that patients have different susceptibilities to high-dose opioid dependence,” said Dr. Streltzer, who is president of the International College of Psychosomatic Medicine.

That doesn’t mean genetic factors aren’t at play, but they may be part of a bigger puzzle involving multiple mechanisms, he suggested.

"It has long been believed that genetic factors are involved in opioid dependence, although which genes are involved and what the mechanisms are is not understood," Dr. Streltzer told Medscape Psychiatry.

"In addition, chronic opioid intake induces changes in the brain itself, changing the way the cells respond. This is thought to involve the development of craving, which in chronic pain patients can be experienced as pain and the need for more pain medicine."

Patients can then in fact become more sensitive to pain — as a result of pain medications themselves. "Numerous reports demonstrate enhanced pain sensitivity results from chronic opioid intake by multiple overlapping mechanisms," Dr. Streltzer said. "Patients in programs to alleviate opioid dependence report that their pain improves."

However, Dr. Tennant said clinicians should not rule out the possibility that patients who say they need high doses may have such genetic abnormalities.

"The bottom line is that when we see a patient who claims to have severe pain and needs a very high dose, we shouldn’t jump to conclusion that this is abuse," Dr. Tennant said. "There may be metabolic factors here that have to be taken into consideration and may explain why these patients may need odd regimens."

Dr. Tennant and Dr. Streltzer have disclosed no relevant financial relationships.

American Academy of Addiction Psychiatry (AAAP) 20th Annual Meeting Symposium: Poster 5. Presented December 4, 2009.