美國政府需要一個關(guān)鍵問題的答案，或許只有雷福德·布朗博士能夠回答：遏制美國阿片類藥物蔓延方面，新款止痛藥奧施康定到底起沒起作用？

布朗是肯塔基大學(xué)的疼痛治療專家，針對重新配置成分以防止吸食和注射的阿片類藥物，負責(zé)領(lǐng)導(dǎo)的外部專家小組為美國食品與藥品管理局（FDA）提供咨詢。

現(xiàn)在只有一個問題：生產(chǎn)奧施康定的公司和FDA都不允許專家查看數(shù)據(jù)，以確定新款奧施康定究竟能否減少濫用。

“過去四五年，為了看數(shù)據(jù)我們申請了大約40到50次，每次都被拒絕。”布朗表示，他在FDA的顧問任期已經(jīng)于3月結(jié)束。

近十年前，F(xiàn)DA批準了新配方的奧施康定，并通知普渡制藥將評估新款是否能夠減少上癮、濫用和死亡病例。由普渡提交的應(yīng)答數(shù)據(jù)仍然保密。

“我們了解藥品原理是為了公眾利益，結(jié)果誰也看不見，認真想想真可怕?！辈祭矢嬖V美聯(lián)社。

2015年，布朗和同事本應(yīng)在華盛頓一場會議上審查奧施康定的后續(xù)數(shù)據(jù)，但就在會議召開的前幾天，F(xiàn)DA宣布取消了該會議。普渡取消遞交奧施康定與濫用相關(guān)的更新信息，聲稱希望有更多的時間來分析數(shù)據(jù)。而此類會議通常提前幾個月便已計劃，幾乎從未取消。

總部位于康涅狄格州斯坦福德的普渡發(fā)言人表示，公司正在努力完成2016年FDA指定的四項新研究要求。公司表示，已經(jīng)提交三份FDA要求的研究報告，預(yù)計10月之前提交最后一份。

“研究完成并經(jīng)FDA審查后，將考慮向科學(xué)界發(fā)布相關(guān)的重要數(shù)據(jù)?！滨U勃·約瑟芬森在一份聲明中表示。

但FDA內(nèi)部負責(zé)阿片類藥物的高層官員去年在公開會議上表示，“數(shù)年前”就希望看到相關(guān)信息。

“公司手上有數(shù)據(jù)，但很難強迫他們提交?！盕DA的止痛藥物部門主管莎倫·赫茲說。

不公布奧施康定數(shù)據(jù)，凸顯了FDA在公共衛(wèi)生機構(gòu)和行業(yè)密友之間不斷搖擺的身份。雖然FDA可以命令藥企研究重要問題，但信息本身仍然屬于公司，并被視為“商業(yè)機密”。

FDA的一位發(fā)言人通過郵件表示，在普渡制藥的研究結(jié)果完全提交和審查之前就發(fā)表評論“為時過早”。FDA指出，奧施康定最終研究結(jié)果將推遲。工作人員預(yù)計，相關(guān)研究“有助于了解奧施康定調(diào)整配方后對濫用的實際影響，”林賽·梅耶表示。

過量服藥死亡

即便奧施康定確實減少了過量服藥導(dǎo)致死亡的案例，聯(lián)邦統(tǒng)計數(shù)據(jù)中也并無體現(xiàn)。

奧施康定仍然是美國最暢銷的阿片類藥物，不過在美國阿片類藥物處方中占比不到2%，可能限制了其對全國趨勢的影響。（大多數(shù)阿片類藥物都是廉價的仿制藥。）

自從2010年批準新配方以來，涉及濫用奧施康定、撲熱息痛和仿制藥等處方阿片藥物致死案例在2017年上升了30%以上，達到約14500人。2017年也是具有完整數(shù)據(jù)最近的一年。兩周前公布的初步數(shù)據(jù)顯示，去年與阿片藥物濫用有關(guān)的死亡人數(shù)可能是數(shù)十年來首次下降。

一些研究人員建議重新調(diào)整奧施康定配方，加之更嚴格的處方和其他措施，加速了全國轉(zhuǎn)向嗎啡和芬太尼。2017年嗎啡和芬太尼導(dǎo)致43000多人因服藥過量死亡，幾乎是處方阿片藥物的三倍。

FDA已經(jīng)批準了7種阿片類藥物，包括奧施康定，還強調(diào)“希望”遏制濫用。

為了防止濫用，很多止痛藥很難碾碎、打破，或溶解，但只要吞進肚子還是能夠濫用。而且各種藥都有上癮的風(fēng)險。

“從公共衛(wèi)生角度來看，阿片類藥物的真正問題是成癮?！绷_格斯大學(xué)急診醫(yī)學(xué)專家劉易斯·納爾遜博士說，他也是FDA的顧問?！案淖兣浞讲⒉荒軌驕p少上癮的可能性，也無法降低上癮程度?！?/p>

普渡制藥已經(jīng)在同行評審的期刊上發(fā)表更改奧施康定配方的初步信息，但相關(guān)研究受潛在偏見和局限性影響。很多內(nèi)容由普渡制藥的科學(xué)家或研究人員撰寫，資金來自于公司。多數(shù)情況下，數(shù)據(jù)來源來自于專門的網(wǎng)絡(luò)，包括毒物控制中心、執(zhí)法記錄和藥物康復(fù)診所。

數(shù)據(jù)來源可以顯示新款奧施康定表現(xiàn)良好，不少關(guān)鍵指標(biāo)，包括緊急呼叫、執(zhí)法報告，以及患者找多個醫(yī)生開處方，也就是所謂的換醫(yī)生比例都在下降。

但即便研究作者也承認，各項指標(biāo)并不一定能夠反映全美國的情況。舉例來說，只有一小部分濫用阿片藥物的人會接受康復(fù)治療。

FDA的研究人員在研究中單獨核查奧施康定的濫用情況，使用規(guī)模更大的數(shù)據(jù)庫，也就是聯(lián)邦政府的年度調(diào)查。這次他們有新發(fā)現(xiàn)。有濫用處方阿片病史的人當(dāng)中，在藥品配方調(diào)整三年內(nèi)濫用奧施康定的比例相似，甚至更高。

“如果想看影響，從這里應(yīng)該就可以看出來。但我們什么也沒有看到?！笨死锼雇懈ァき偹共┦空f，他與人合著了2017年的報告，如今在疾病控制和預(yù)防中心工作。

報告的發(fā)現(xiàn)與調(diào)查結(jié)果一致，顯示在配方調(diào)整后，放棄奧施康定的長期濫用者不到5%。

洛杉磯的加勒特·哈德說，之前阿片藥物上癮時，他只需要在廚房里花上幾分鐘就可以準備好奧施康定，然后注射。

“最后變成‘日常注射沒關(guān)系，反正奧施康定可以防濫用?！?2歲正在康復(fù)中的哈德說。

奧施康定的持續(xù)成本

奧施康定最早于1996年推出，后來掀起了濫用浪潮，因為有些人很快學(xué)會了將長效緩釋的藥片弄碎，獲得大量阿片成分。在監(jiān)管機構(gòu)、政界人士和執(zhí)法部門壓力下，2010年普渡制藥采取了新設(shè)計。

兩周前公布的政府?dāng)?shù)據(jù)顯示，2006年至2012年期間，普渡和其他藥企在美國出售了超過760億片阿片藥物。銷量最多的地區(qū)濫用率也最高。

如今，普渡面臨著2000多起地方和州一級訴訟，指控其淡化奧施康定成癮風(fēng)險，積極市場推廣，并稱之適用于普通的疼痛管理，最終導(dǎo)致阿片藥物蔓延。面臨多重訴訟，公司還公開討論過破產(chǎn)問題。

調(diào)整藥品配方提振了業(yè)務(wù)。

最初版奧施康定的專利在2013年到期，價格低廉的仿制藥就能夠搶走普渡的市場份額。通過調(diào)整配方，普渡將專利延長到2030年。

藥品跟蹤服務(wù)公司IQVIA稱，2010年以來奧施康定在美國的銷售額已經(jīng)超過210億美元。

推廣材料顯示，普渡認為新配方的防濫用功效是“關(guān)鍵推動力”，向醫(yī)生推銷時也不斷強調(diào)。面臨越發(fā)嚴格的審查，去年普渡已經(jīng)停止直接向醫(yī)生推銷奧施康定。

與此同時，數(shù)據(jù)公司Elsevier的數(shù)據(jù)顯示，普渡已經(jīng)將奧施康定的價格穩(wěn)步提高了超過95%，服用最高劑量的話達到每片22美元。

至于該藥的防濫用特性值不值得付出更高成本，一直在爭論中。

非營利組織臨床和經(jīng)濟評論研究所發(fā)現(xiàn)，奧施康定防濫用方面其實并無定論。

FDA的前高級官員彼得·盧里博士與他人合著了2017年的報告，發(fā)現(xiàn)長期使用奧施康定的人濫用行為基本上沒有變化。

如今擔(dān)任非營利組織公益科學(xué)中心主席的盧里指出，奧施康定是迄今為止處方量最大、被研究最多的防濫用阿片藥物。

“如果無法證明奧施康定能夠防止濫用，如何證明其他藥有此作用？”他問道。（財富中文網(wǎng)）

譯者：馮豐

審校：夏林

Dr. Raeford Brown was uniquely positioned to help the U.S. government answer a critical question: Is a new version of the painkiller OxyContin helping fight the national opioid epidemic?

An expert in pain treatment at the University of Kentucky, Brown led a panel of outside experts advising the Food and Drug Administration on opioids that have been reformulated to deter snorting and injecting.

There's just one problem: Neither the company that makes OxyContin nor the FDA has allowed the experts to see data on whether it reduces abuse.

“We asked for that data probably 40 or 50 times in last four or five years and were denied every time,” said Brown, whose term as an FDA adviser ended in March.

Nearly a decade ago, the FDA approved reformulated OxyContin and told the company, Purdue Pharma, that it would be evaluated on whether the new version decreased cases of addiction, overdose and death. The data submitted by Purdue to answer that question remains secret.

“It's in the public interest that we all know what these drugs are doing and yet none of us can see it, which is really terrifying when you think about it,” Brown told The Associated Press.

In 2015, Brown and his colleagues were supposed to review follow-up data on OxyContin at a meeting in Washington, but the FDA canceled it only days before. Purdue had pulled its application to update OxyContin's label with new information on abuse, saying it wanted more time to analyze the data. Such meetings are typically planned months in advance and are almost never canceled.

A Purdue spokesman said the Stamford, Conn.-based company has been working to complete four updated study requirements assigned by the FDA in 2016. The company said it has submitted three of the FDA-mandated studies and expects to submit the final one by October.

“Once all of the studies are completed and FDA has had the opportunity to review the results, we will evaluate options to disseminate this important data to the scientific community,” said Bob Josephson, in a statement.

But the FDA's top staffer for opioids said at a public meeting last year that the agency expected the information to become available “years ago.”

“They have it, but it's hard for us to force them to submit it,” said Sharon Hertz, FDA's division director for pain medications.

The unreleased OxyContin data highlights the FDA's precarious role as both a public health agency and close confidante of industry. While the agency can order a drugmaker to research important questions, the information itself still belongs to the company and is deemed “confidential commercial information.”

An FDA spokeswoman said in an email that it would be “premature” to comment on Purdue's results before they have been fully submitted and reviewed. The agency noted that the company's final OxyContin study has been delayed. FDA staffers expect the studies “will help us understand the real-world impact of OxyContin's reformulation on abuse,” said Lyndsay Meyer.

Overdose deaths

If OxyContin has reduced overdose deaths, federal statistics don't show it.

OxyContin remains the best-selling opioid brand in the country, but it accounts for less than 2% of U.S. opioid prescriptions, potentially limiting its impact on national trends. (Most opioids prescribed are low-priced generic pills.)

Since the new formulation was approved in 2010, fatal overdoses involving prescription opioids including OxyContin, Percocet, and generic pills have risen more than 30% to about 14,500 in 2017, the most recent year for which complete data is available. Preliminary figures released two weeks ago suggest drug-related deaths likely fell last year for the first time in decades.

Some researchers have suggested reformulated OxyContin, combined with tighter prescribing and other measures, accelerated the nationwide shift toward heroin and fentanyl. Those drugs were involved in more than 43,000 overdose deaths in 2017, nearly three times the number as prescription opioids.

The FDA has now approved seven opioids, including OxyContin, with labeling that they are “expected” to discourage abuse.

Those pills are intended to be difficult to crush, break, or dissolve, but they can still be misused when simply swallowed. And the drugs carry the same addiction risks.

“The real problem with opioids from the public health perspective is addiction,” said Dr. Lewis Nelson, a Rutgers University emergency medical specialist who also serves as an FDA adviser. “These pills in the reformulated version don't do anything to reduce the likelihood or magnitude of addiction.”

Purdue has published preliminary information on reformulated OxyContin in peer-reviewed journals, but the studies are clouded by potential biases and limitations. Many are written by Purdue scientists or researchers whose work is funded by the company. In most cases, the data comes from a network of specialized sources, including poison control centers, law enforcement records and drug rehabilitation clinics.

Those sources show a positive picture for OxyContin's performance, with key indicators like emergency calls, law enforcement reports, and rates of patients seeking prescriptions from multiple prescribers—known as doctor shopping—dropping.

But even the study authors acknowledge that those measures don't necessarily reflect what's happening across the country. Only a small segment of people misusing opioids ever enter rehabilitation, for instance.

When FDA researchers decided to independently examine OxyContin abuse in a study using a much larger dataset—a federal government annual survey—they found a different picture. Among people with a history of misusing prescription opioids, rates of OxyContin abuse were similar or higher three years after the drug was reformulated.

“If you were going to see an impact, this is the population where you should see it. And we didn't see anything,” said Dr. Christopher Jones, who co-authored the 2017 paper and now works at the Centers for Disease Control and Prevention.

The paper's findings square with survey results suggesting less than 5% of long-term abusers gave up OxyContin after it was reformulated.

Garrett Hade of Los Angeles said that when he was addicted to opioids it would take him only a few minutes in his kitchen to prepare OxyContin for injecting.

“It just became a matter of 'this is what you have to do today because you have abuse-deterrent OxyContin,'” said Hade, 32, who is in recovery.

The continuing cost of OxyContin

First launched in 1996, the original OxyContin helped spark a wave of abuse as some people quickly learned to crush the long-acting pills to release a massive opioid dose. Under pressure from regulators, politicians and law enforcement, Purdue reformulated the painkiller in 2010.

Government data unveiled two weeks ago showed Purdue and other drugmakers flooded the U.S. with more than 76 billion opioid pills between 2006 and 2012. Areas that received the most pills also had the highest overdose rates.

Today, Purdue faces some 2,000 local and state lawsuits alleging its aggressive marketing contributed to the opioid epidemic by downplaying OxyContin's addiction risks and promoting the drug for common pain ailments. The lawsuits have pushed the company to publicly discuss bankruptcy.

The reformulation has been good for business.

The patent on original OxyContin would have expired in 2013, allowing lower-priced generics to gobble up Purdue's market share. By reformulating the drug, Purdue was able to extend its patent until 2030.

Since 2010, OxyContin has generated more than $21 billion in U.S. sales, according to pharmaceutical tracking service IQVIA.

Purdue viewed the anti-abuse reformulation as a “key driver” of new prescriptions and stressed the features in promotions to doctors, according to its marketing materials. Purdue stopped promoting OxyContin directly to doctors last year amid mounting scrutiny.

Meanwhile Purdue has steadily increased OxyContin's price more than 95 percent, to $22 per pill for the drug's highest dose, according to data firm Elsevier.

Whether the drug's anti-abuse features warrant those costs has been debated.

The nonprofit group Institute for Clinical and Economic Review has found mixed evidence for OxyContin's ability to fight abuse.

Dr. Peter Lurie, a former FDA senior official, co-authored the 2017 paper that found OxyContin misuse was essentially unchanged among long-term users.

Now president of the nonprofit Center for Science in the Public Interest, Lurie notes that OxyContin is by far the most prescribed and most studied abuse-deterrent opioid.

“If we can't prove it for OxyContin, how are we going to show it for anything else?” he asked.