An addictive product which devastates lives is heavily promoted by an industry that underplays or denies its potential for dependence or risk of harm and buys political influence to oppose regulation. Not cigarettes, but prescription opioids, which have killed more than a third of a million Americans this century. How has this been allowed to happen and what are the lessons?

The story, as set out in Chris McGreal’s powerful account “American Overdose” starts with good intentions. Following the US Civil War morphine addiction became common, especially with the invention of the hypodermic syringe. A backlash led to a powerful taboo against opiate use. Think of Mrs Dubose, determined to die morphine free (and presumably in pain), in “To Kill a Mockingbird.”

These attitudes were preventing the effective delivery of palliative care. Weak evidence which suggested that opioid addiction was rare in people taking the medications for pain who did not have a history of addiction, and was intended to encourage a reassessment of this prejudice, was instead weaponised by the pharmaceutical industry with horrific consequences. [1]

The high potency slow release opioid, OxyContin, initially received a marketing license for moderate to severe chronic pain, despite an absence of evidence of effectiveness for this indication. This was accompanied by a comment about low risk of addiction, based on its slow release formulation. There was no evidence to support this either, the assertion having arisen from the manufacturer’s marketing department. A doctor in Grant County, West Virginia describes how pharmaceutical representatives “had a New England Journal of Medicine article saying that people don’t get addicted. If they have legitimate pain, they don’t get addicted. They got handed out to every doctor”. This was too good to be true, and of course it wasn’t.

In poor areas where people had lived hard lives, pain clinics, effectively “pill factories” began to appear. Patients might see a doctor only once for a cursory consultation, then collect monthly repeat prescriptions, signed in advance, illegally.  Doses were escalated automatically as vulnerable patients became more dependent. People travelled from far and wide, often visiting multiple establishments. Although the OxyCodone was in a slow release form, once crushed the pills could be injected or inhaled for a rapid effect. They were advised only to attend certain pharmacies, both to avoid scrutiny and because they were owned by the same individuals as the clinics, allowing profits both from consultation fees and for dispensing.

The book details how despite an obvious and growing problem, including dealing in clinic parking lots, law enforcement agencies were reluctant or uncertain about intervention in apparently legal medical activity. Legislators protected the pharmaceutical industry as profits and donations multiplied. Measures to rein in supply by enforcing scrutiny of unusual patterns of distribution—massive deliveries to small towns—were obstructed. As with tobacco, the most vulnerable were blamed for becoming addicted.

Meanwhile, expert groups and charities, some in receipt of pharmaceutical funding or established by the pharmaceutical industry, promoted the conception of pain as a “5th vital sign”. Well intended perhaps, but the adoption of this as a metric drove a huge increase in opioid use. Sales reps pressured more reluctant doctors to match the “compassionate and professional” behaviour of high prescribing peers.

Professional bodies come out of this poorly too, having rejected calls for compulsory education about the addiction risk of opiates for doctors. They also opposed the introduction of systems to register users of opiates to prevent clinic-hopping.

There is at least now a clear recognition that there is a problem, fines (small ones) have been issued and some healthcare professionals have gone to prison. In 2007, the manufacturer of OxyContin and three senior executives pleaded guilty to federal criminal charges that they misled regulators, doctors, and patients about the risk of addiction associated with the drug. [2] High dose opiates are recognised as poorly effective in chronic pain and indeed may aggravate it. [3] Nevertheless, deaths continue, not least because, as McGreal describes, opiate addicted individuals are switching to heroin which may be cheaper, but, cut with fentanyl, can have a highly variable potency increasing the risk of overdose. [4]

A final parallel with tobacco—pharmaceutical companies are now looking “to the developing world for new markets as prescribing of opioids comes under increasing scrutiny in the richer nations”.

So what are the lessons? First, a commercial healthcare system increases the risk that doctors succumb to financial incentives to the detriment of their patients. The most vulnerable suffer the most. It also risks distorting the behaviour of regulators, as does a revolving door between regulated and regulators.

Second, arguments about risks and benefits should be framed honestly and not exaggerated or underplayed to “shift perceptions”. Expert groups set up by the pharmaceutical industry are likely to serve the interests of the pharmaceutical industry. The same goes for charitable groups.

Third, we need to be cautious about therapeutic drift. In addition to opioids, increasing numbers of people are on gabapentin or pregabalin—themselves now drugs of dependence. Some evidence suggests that claims for medicinal cannabis are running a long way ahead of the evidence.

As with Ben Goldacre’s “Bad Pharma”—none of the individual types of bad behaviour are that surprising, but the assembled package is shocking. American Overdose is a tale of bad decision making, greed and malfeasance that is still unfolding, and not one about which we can afford to be complacent.

Nick Hopkinson, reader in respiratory medicine, Imperial College London, and medical director of the British Lung Foundation.

Competing interests: None declared.

References:

1 Porter J, Jick H. Addiction Rare in Patients Treated with Narcotics. New England Journal of Medicine 1980; 302:123-123

2 Leung PTM, Macdonald EM, Stanbrook MB, et al. A 1980 Letter on the Risk of Opioid Addiction. New England Journal of Medicine 2017; 376:2194-2195

3 Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical TrialOpioid vs Nonopioid Medications on Pain-Related FunctionOpioid vs Nonopioid Medications on Pain-Related Function. JAMA 2018; 319:872-882

4 Cicero TJ, Ellis MS, Surratt HL, et al. The Changing Face of Heroin Use in the United States: A Retrospective Analysis of the Past 50 YearsChanging Face of Heroin Use in the United StatesChanging Face of Heroin Use in the United States. JAMA Psychiatry 2014; 71:821-826

5 Keyhani, S., S. Steigerwald, J. Ishida, M. Vali, M. Cerdá, D. Hasin, C. Dollinger, S. R. Yoo and B. E. Cohen (2018). “Risks and Benefits of Marijuana Use: A National Survey of U.S. AdultsRisks and Benefits of Marijuana Use: A National Survey of U.S. Adults.” Ann Intern Med 2019 169(5): 282-290.