The Great American Drug Deal

by Peter Kolchinsky

  Insurance Companies’ Response

  Insurance companies, under no obligation to favor newer abuse-deterrent opioids over older generic ones and with an eye on their own bottom line, still set low copays for generic opioids and high ones for branded versions, nudging patients away from newer technologies. Purdue offered PBMs rebates on OxyContin, so even when a drug like Xtamptza ER came along that would be harder to abuse, insurance steered physicians and patients considering a long-acting opioid towards OxyContin. Insurance companies may have felt justified in not valuing incremental, abuse-deterring upgrades based on cost-effectiveness analyses published by academics that suggested they weren’t worth it, but such studies fail to consider the lives that will continue to be saved long after upgraded versions go generic.409

  Nor did many physicians, secure in their “not my patients” mindset, feel compelled to switch to prescribing abuse-deterrent opioids. Selecting an abuse-deterring branded for a patient meant both insinuating that the patient might become a drug abuser and sticking them with a higher copay as the cost of this mistrust.

  Other than OxyContin, the few other abuse-deterrent opioids that the FDA approved did not sell well, and investors began to pull back from funding similar projects.410 Investors and innovators either didn’t know how high the FDA’s bar was for considering an upgraded opioid meaningfully safer than OxyContin or didn’t see a way to achieve that goal. But even if there had been a technological way to make opioids non-abusable, that would not have helped everyone already addicted to them. In fact, just the limited abuse-deterrent features built into OxyContin had immediate, lethal, unintended, yet predictable consequences.

  All Roads Lead Here

  Operating under a false sense of security, the FDA, physicians, and drug companies directed countless patients towards an on-ramp to addiction for over a decade.411 As they realized their mistakes and made changes, the death rate from prescription opioids began to fall.412 But tighter prescribing rules and the switch to abuse-deterrent opioids in 2010 pushed great numbers of people addicted to OxyContin into the street, where they began to overdose in unprecedented numbers on more potent, adulterated, and unmarked opioids, especially heroin and illicit synthetic fentanyl.413 By 2010, a study even showed a rise in the rate of hepatitis C infections associated with the uptick in people injecting heroin.414 The only way to help all of the people who had become addicted was to treat their addiction.

  Fortunately, there has been some progress in the development of treatments for opioid abuse. Drugs like naloxone counteract opioids to save the life of someone experiencing overdose, and milder opioids like buprenorphine more safely blunt cravings to help patients manage symptoms as they fight to get clean. And thanks to the steady decriminalization of drug possession, it has become easier to treat users as patients suffering from an addiction disorder instead of as criminals. However, we still need insurance reforms to ensure that effective treatments for addiction are as accessible and affordable to all patients as the opioids to which they first became addicted.415

  There can be no diminishing the responsibility that Purdue and other drug companies bear for unethical marketing tactics, along with some physicians who knowingly sold prescriptions to addicts and distributors that did nothing to stop some pharmacies from dispensing more opioid prescriptions than there were people in their neighborhoods.416 They ruined lives. Hopefully large financial fines and settlements and even criminal convictions will drive lasting reforms. But if that’s all we take away from the opioid crisis, then we’ve not learned enough.

  I think we have to acknowledge that these bad actors did not so much cause the crisis as inflame what began with good people making well-intentioned decisions.

  Unattainable Balance

  Even if Purdue had only marketed OxyContin exactly as the FDA allowed in 1995, we would still be dealing with an opioid crisis. The on-label benefit-risk of OxyContin and opioids in general failed to convey how addictive this class of drugs has always been, even when prescribed by well-meaning physicians to patients in real pain. We lied to ourselves about the dangers of pharmaceutical opioids for decades, not unlike how we lied to ourselves about the dangers of smoking and, more recently, vaping,417 by first assuring ourselves these products were safe and later realizing they weren’t.

  That doesn’t mean that pharmaceutical-grade opioids haven’t been profoundly useful medicines. While I would like to believe that I would not have defended the benefits of cigarettes in the 1970s, as cigarette companies notoriously did, I do now defend the importance of opioid drugs in the treatment of pain.418 I appreciate that well-meaning physicians and FDA staff thought they were helping millions of patients suffering from pain by making opioids more accessible.419

  As long as we continue to need opioids to manage pain, we’ll struggle to manage the addiction they inflict. Despite all the attention to the opioid crisis, changes to drug labels, and tightening of both marketing and prescribing practices, in 2017, about 11 million people in the US misused these drugs—a third of these under a prescription from a doctor and nearly half by obtaining, buying, or stealing the drug from a friend or relative with a prescription.420 Opioid labels can be written to urge even more caution, though they are already intimidating, just as the FDA still continues to push for more gruesome labels for cigarettes.421 And I have no doubt that there are still physicians who aren’t prescribing opioids in the most responsible way and need training in some cases or policing in others. But even if there were a single best way to use these drugs, it would still carry a risk of addiction.

  One way or another, I think all roads would have eventually led us to this point where we must acknowledge that we have not yet found a way to manage severe pain that doesn’t also risk destroying lives. Perhaps it’s because I’m a scientist and have witnessed what we can achieve with biotechnology, but the only solution I see to both treating pain and resolving the opioid crisis lies in biomedical innovation.

  Now Where?

  Going forward, we must go beyond simply trying to make opioids harder to abuse. We must gain a greater understanding of the biology of how we experience pain and invest in the development of new types of drugs to reduce pain without addiction. That work is already happening at university laboratories and companies around the world. Whether investors will back these efforts depends on whether they believe that those who succeed in making a non-addictive pain drug will be rewarded, which requires not only physicians wanting to prescribe the drug, but insurance companies being willing to pay for the drug without imposing a higher copayment than for generic opioids.

  It wouldn’t even take anything as dramatic as new legislation imposing drug price controls to rob us of the benefits of non-addictive pain drugs. Just consider how counterproductive it would be—how potentially harmful to society—if, once OxyContin goes generic, insurance companies encouraged patients to save money by taking that instead of making a new non-addictive alternative at least as affordable.

  This is a critical moment, and if we fail to uphold the Biotech Social Contract to encourage the drug industry to solve pain management in a better way, we’ll pay for our short sightedness with many more generations pushed into addiction by old opioid pharmaceuticals.

  * * *

  354GAO, “Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem,” (report to Congressional requesters, Washington D.C., 2013), https://www.govinfo.gov/content/pkg/GAOREPORTS-GAO-04-110/pdf/GAOREPORTS-GAO-04-110.pdf;

  Commonwealth of Massachusetts v. Purdue Pharma L.P. et al., 1184 C.V. 01808 (2019) (Mem.), https://www.documentcloud.org/documents/5684879-Mass-AGO-Pre-Hearing-Memo-and-Exhibits.html.

  355Patrick Radden Keefe, “The Family That Built an Empire of Pain,” The New Yorker, Oct. 23, 2017, https://www.newyorker.com/magazine/2017/10/30/the-family-that-built-an-empire-of-pain.

  356United States General Accounti
ng Office, “Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem” (report number GAO-04-110, Washington D.C., 2004), https://www.gao.gov/htext/d04110.html.

  357“Purdue Pharma Announces Agreement in Principle on Landmark Opioid Litigation Settlement,” Purdue, Sept. 16, 2019, https://www.purduepharma.com/news/2019/09/16/purdue-pharma-announces-agreement-in-principle-on-landmark-opioid-litigation-settlement/.

  358J&J has entered multiple settlements of opioid lawsuits, including a $4 billion agreement in October 2019.

  359Those three distributors account for the overwhelming majority of market share and in October 2019 were said to be paying $18 billion in a settlement of major opioid litigation.

  360Jonathan Stempel, “Drug Firms Must Face Trial Over Opioids, Judge Orders,” Insurance Journal, Sept. 4, 2019, https://www.insurancejournal.com/news/national/2019/09/04/538781.htm.

  361The settlements announced also include companies providing free addiction-treatment drugs, services, and supplies valued at $25-30 billion.

  362Constipation, addiction, and respiratory depression are examples of opioid side effects.

  363Wikipedia Contributors, “List of Largest Pharmaceutical Settlements,” Wikipedia, The Free Encyclopedia, accessed Oct. 15, 2019, https://en.wikipedia.org/wiki/List_of_largest_pharmaceutical_settlements.

  364Red scorpion venom activates proteins called alpha-receptors, so the realization that prazosin functions by blocking alpha-receptors led to the idea that it could help treat people who have been stung.

  365Simon Kung et al., ‘Treatment of Nightmares with Prazosin: A Systematic Review,” Mayo Clinic Proceedings 87, no. 9 (2012): 890-900, Oct. 15, 2019. doi: 10.1016/j.mayocp.2012.05.015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538493/.

  366Murray A. Raskind, “The a1-Adrenergic Antagonist Prazosin Ameliorates Combat Trauma Nightmares in Veterans with Posttraumatic Stress Disorder: A Report of Four Cases,” The Journal of Clinical Psychiatry 61, no. 2 (2000): 129-33, Oct. 15, 2019. https://www.ncbi.nlm.nih.gov/pubmed/10732660.

  367Pfizer Labs, Minipress Capsules: Prazosin Hydrochloride (New York: Pfizer Inc., 2019), https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017442s033lbl.pdf

  368Of course, with no DTC campaign in effect, patients are less likely to know about it. Furthermore, psychiatrists and other specialists who deal with trauma are more likely to know about prazosin’s off-label usage than primary care physicians (PCPs), which means that patients who might benefit from this treatment might require a referral to expensive specialists from their PCPs before this treatment is even discussed.

  369“Food and Drug Administration Amendments Act (FDAAA) of 2007,” US Food & Drug Administration, March 29, 2018, https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-administration-amendments-act-fdaaa-2007.

  370“Drug Facilitated Sexual Assault,” Science Direct, Elsevier, accessed Oct. 15, 2019, https://www.sciencedirect.com/topics/medicine-and-dentistry/drug-facilitated-sexual-assault.

  371Trinka Porrata, “GHB Death Statistics,” Project GHB, accessed Oct. 15, 2019, http://www.projectghb.org/content/ghb-death-statistics.

  372Wikipedia Contributors, “Date Rape Drug,” Wikipedia, The Free Encyclopedia, accessed Oct. 15, 2019, https://en.wikipedia.org/wiki/Date_rape_drug

  373Reviewed by L. Anderson, “List of Schedule 1 Drugs,” Drugs.com, updated May 18, 2018, https://www.drugs.com/article/csa-schedule-1.html.

  374XYREM, Patient Quick Start Guide (Jazz Pharmaceuticals, 2019), https://www.xyremrems.com/assets/files/Xyrem_REMS_Patient_Quick_Start_Guide_PDF_final_press.pdf.

  375Y. Grace Wang et al., “Safety Overview of Postmarketing and Clinical Experience of Sodium Oxybate (Xyrem): Abuse, Misuse, Dependence, and Diversion,” Journal of Clinical Sleep Medicine 5, no. 4 (2009): 365-71, Oct. 15, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725257/.

  376Gamma Hydroxybutyric Acid (Drug Enforcement Administration, 2018), https://www.deadiversion.usdoj.gov/drug_chem_info/ghb.pdf. ;

  Wikipedia Contributors, “Date Rape Drug.”

  377“Narcolepsy Fast Facts,” Narcolepsy Network, revised June 2015, https://narcolepsynetwork.org/about-narcolepsy/narcolepsy-fast-facts/;

  Second Quarter 2019 Financial Results (Jazz Pharmaceuticals, 2019), https://investor.jazzpharma.com/static-files/af719763-9e0a-4ada-8ab9-b22c52c8c22c;

  “Prevalence,” National Fibromyalgia Association, accessed Oct. 15, 2019, http://www.fmaware.org/about-fibromyalgia/prevalence/.

  378Roland Staud, “Sodium Oxybate for the Treatment of Fibromyalgia,” Expert Opinion on Pharmacotherapy 12, no. 11 (2011): 1789-98, accessed Oct. 15, 2019. doi: 10.1517/14656566.2011.589836, https://www.ncbi.nlm.nih.gov/pubmed/21679091.

  379Michael J. Brownstein, “A Brief History of Opiates, Opioid Peptides, and Opioid Receptors,” Proc. Natl. Acad. Sci. 90 (1993): 5391-93, accessed Oct. 15, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46725/pdf/pnas01469-0022.pdf.

  380Chandrasekhar Krishnamurti and SSC Chakra Rao, “The Isolation of Morphine by Serturner,” Indian Journal of Anaesthesia 60, no. 11 (2016): 861-2, accessed Oct. 15, 2019. doi: 10.4103/0019-5049.193696, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125194/.

  381Leung et al., “Addiction Rare in Patients Treated with Narcotics,” New England Journal of Medicine 302, no. 123 (1980), accessed Oct. 15, 2019. doi: 10.1056/NEJM198001103020221, https://www.nejm.org/doi/10.1056/NEJM198001103020221.

  382This drug classes included methadone, hydromorphone, hydrocodone, oxymorphone, oxycodone, and fentanyl, many of which were available in various formulations and combinations.

  383The American Pain Society was named as a defendant in the major opioid litigation and subsequently declared bankruptcy in 2019.

  384James N. Campbell, “APS 1995 Presidential Address” (speech, Los Angeles, Nov. 12, 1995) The Journal of Pain, https://www.jpain.org/article/S1082-3174(96)80076-6/abstract.

  385Therein quoting Campbell: “Vital Signs are taken seriously. If pain were assessed with the same zeal as other vital signs are, it would have a much better chance of being treated properly. We need to train doctors and nurses to treat pain as a vital sign. Quality care means that pain is measured and treated.”

  386“Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse,” US Food & Drug Administration, updated Sept. 25, 2019, https://www.fda.gov/drugs/information-drug-class/timeline-selected-fda-activities-and-significant-events-addressing-opioid-misuse-and-abuse.

  387Marcia Angell, “Opioid Nation,” The New York Review of Books, Dec. 6, 2018, https://www.nybooks.com/articles/2018/12/06/opioid-nation/.

  388GAO, “Prescription Drugs.”;

  Commonwealth of Massachusetts v. Purdue Pharma L.P. et al., 1184 C.V. 01808 (2019) (Mem.), https://www.documentcloud.org/documents/5684879-Mass-AGO-Pre-Hearing-Memo-and-Exhibits.html.

  389GAO, “Prescription Drugs.”

  390GAO, “Prescription Drugs.”

  391Wikipedia Contributors, “List of Largest Pharmaceutical Settlements.”

  392Heather Won Tesoriero, “OxyContin Maker Pleads Guilty,” The Wall Street Journal, May 11, 2007, https://www.wsj.com/articles/SB117880640850298612.

  393Patrick Radden Keefe, “The Family That Built an Empire of Pain.”

  394James C. Crews and Donald D. Denson, “Recovery of Morphine From a Controlled-Release Preparation: A Source of Opioid Abuse,” Cancer 66 (1990): 2642-4, accessed Oct. 15, 2019. https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142(19901215)66:12%3C2642::AID-CNCR2820661229%3E3.0.CO;2-B.

 
395“Timeline of Selected FDA Activities,” US Food & Drug Administration.

  396At this point, you may see the parallel to Xyrem, which was more like MS Contin when used just for the small population of narcolepsy patients but threatened to be more like OxyContin if approved for fibromyalgia. In 2010, when considering whether to approve Xyrem for fibromyalgia, the FDA exhibited far more caution than it did in 1995 with regard to opioids.

  397“Overdose Death Rates,” National Institute on Drug Abuse, USA.Gov, updated Jan. 2019, https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates.

  398Marilyn Bulloch, “How Oxycodone Has Contributed to the Opioid Epidemic,” Pharmacy Times, Aug. 2, 2018, https://www.pharmacytimes.com/contributor/marilyn-bulloch-pharmd-bcps/2018/08/how-oxycodone-has-contributed-to-the-opioid-epidemic.

  399Acetaminophen is the active ingredient in Tylenol.

  400“What New Opioid Laws Mean for Pain Relief,” Harvard Health Publishing, Oct. 2018, https://www.health.harvard.edu/pain/what-new-opioid-laws-mean-for-pain-relief;