by Christopher Gerry
figures by Michael Gerhardt

One of the sad ironies of modern medicine is that painkillers, licit and illicit alike, have brought addiction, suffering, and death to communities across the United States. The prevalence of opioid abuse in particular has skyrocketed over the past few years and shows few signs of abating. In 2014, the most recent year for which the Centers for Disease Control and Prevention (CDC) has data, roughly 2.5 million Americans abused opioids and almost 30,000 deaths were attributed to opioid overdoses, a number that’s tripled since 2000.

Just in time for election season, legislators from all tiers of government have begun to respond. Proposed measures include changing the way that doctors prescribe opioids, disrupting the supply of illicit drugs, and expanding access to drugs that can reverse opioid overdoses. But which of these strategies is the most effective? For that matter, do any of them actually work? The science of opioid abuse can provide critical insights into these questions so that we can fund the most effective treatment options and maximize our chances of resolving this mounting crisis.

Genesis – The Birth of the Opioid Crisis

Fixtures in medicine for thousands of years, opioids like morphine and heroin are powerful painkillers that change the way that our bodies respond to pain (Figure 1). Unlike over-the-counter painkillers like Advil, which typically block the production of chemicals that promote inflammation and fever, opioids derive their profound analgesic effects by acting directly in the brain and muting the propagation of pain signals. But however useful opioids may be, their notorious side effects cannot be ignored. Opioid users often suffer from constipation and nausea, and doctors must employ careful dosage regimens to stave off dependence, addiction, and abuse. Potentially fatal overdoses can occur if opioids flood the brain and suppress the signals that regulate breathing.

Figure 1: Opioids and Aspirin Reduce Pain in Different Ways. The figure above is a cartoon representation of how different painkillers achieve their therapeutic effects. A nonsteroidal anti-inflammatory drug like aspirin inhibits the body’s synthesis of chemicals called prostaglandins, which is an indirect way of reducing inflammation, swelling, and pain. Opioids, on the other hand, make the nervous system less effective at transmitting pain signals, so the signals that do make it to the brain are less intense.

Physicians’ uneasy relationship with opioids started to spiral out of control in the late 20th century. As the potential dangers of opioid use became more apparent throughout the 1900s, “opiophobia” seeped into clinics around the country. As a result, a federal study in 1992 found that half of surgical patients didn’t have their pain properly managed. Spurred into a dramatic overcorrection by both the government and their oath to “do no harm,” physicians tripled the number of opioid prescriptions they wrote from 1991 to 2013. Unfortunately, initial attempts to curb the resulting rise in prescription opioid abuse unintentionally sent many addicts flocking to illicit opioids like heroin, resulting in a three-fold increase in annual heroin deaths from 2010 to 2014.

The severity of the opioid crisis is further compounded by the lack of effective treatment options. Administration of drugs like methadone can subdue cravings and fend off withdrawal symptoms, but methadone is in itself an addictive opioid that’s saddled with many of the side effects of the drugs it’s meant to supplant. Furthermore, addiction remains a poorly understood and highly stigmatized disease. Developing a therapeutic strategy is difficult when you can’t identify your target, but thorough analysis of clinical data can suggest where to aim first.

Fighting Fire with Fire – The Science of Opioid Abuse

For all of its shortcomings, medication-assisted treatment (MAT) strategies that combine traditional psychosocial therapy with careful opioid administration remain some of the most promising options for curbing opioid abuse. A 2009 review of 11 randomized clinical trials and their 1,969 participants compared the effects of methadone, which is commonly used in MAT, to either placebo- or non-medication-based treatments. Overall, about 60% of patients who received methadone stayed in treatment and abstained from heroin use throughout the study, which is roughly twice the rate of patients who received other therapies.

A broader review from 2015 found additional evidence for MAT’s efficacy. Five studies and reviews, including the one described above, were examined simultaneously to generate a dataset that comprised 3,350 patients and three varieties of MAT. In all cases, MAT patients were at least 56% more likely to stay clean than their non-MAT counterparts, with abstinence rates ranging from 20% to 60% (Figure 2). These data also suggest that a mixture of opioids called buprenorphine and naloxone may be comparable to methadone, which is the current “gold standard” for treating opioid abuse.

Figure 2: Medication-assisted treatment works.
Figure 2: Clinical Evidence Supports MAT-Based Treatments. The graph above shows data from four separate clinical trials comparing the effectiveness of MAT-based treatments (with methadone, buprenorphine, and/or naloxone) to those that did not incorporate medication. The values shown in the graph represent the percentage of patients who abstained from illicit opioid use over the entire course of the clinical trial. In all four cases, the MAT-based treatment resulted in a significantly higher opioid abstinence rate compared to placebo. Data obtained from Connery’s 2015 study in the Harvard Review of Psychiatry.

While MAT appears to be reasonably effective at reducing illicit opioid use, freeing patients from opioids altogether remains the ultimate goal. Treatments that include drugs like methadone are sometimes pejoratively called “replacement therapy” or “substitution therapy” because swapping street drugs for prescription narcotics doesn’t necessarily address the underlying biology. As a result, users remain subjected to the deleterious side effects that are common to all opioids, and they often continue to suffer from addiction. Opioid addiction is a drug-induced alteration to the brain’s reward center that leads patients to compulsively and pathologically engage in further substance abuse. Direct treatments for addiction remain elusive, so slowly weaning MAT patients off of their FDA-approved opioid(s) remains a common long-term goal.

Methadone, buprenorphine, and naloxone—three of the most common MAT drugs—interact with the brain in different ways (Figure 3). Methadone is a full agonist of the μ-opioid receptor, which means that it activates the same part of the brain that’s targeted by illicit opioids like heroin, doing so with similar potency. One key difference, however, is that orally-dosed methadone is released slowly into the blood stream. Therefore, it’s less susceptible to abuse because it doesn’t produce the short-term euphoric effects that characterize heroin injection. Buprenorphine is similar to methadone in several ways—both drugs are commonly used in long-term treatment plans—but it’s only a partial agonist of the μ-opioid receptor, so the brain’s response is less dramatic. Naloxone, on the other hand, is most often used to reverse opioid overdoses in emergency situations. Instead of activating the μ-opioid receptor, naloxone is an inverse agonist, which re-sensitizes the brain to the signals that most opioids deaden. Importantly, this effect can save a patient’s life if breathing becomes compromised during an overdose.

Figure 3
Figure 3: Opioids Can Elicit a Wide Variety of Physiological Responses. The figure above summarizes the physiological effects of (clockwise from top-right) heroin, naloxone, buprenorphine, and methadone on both individual brain cells and the human body as a whole. Opioids’ effects arise largely from their interactions with the μ-opioid receptor (depicted as a black “Y”), which is found throughout the central nervous system. While heroin is a strong activator of this receptor and can provoke dramatic feelings of euphoria, drugs commonly used in MAT typically do not elicit this response and, thus, are less prone to abuse.

Strong conclusions regarding ideal treatment strategies are rare, but several themes continue to populate the literature. First, MAT’s pairing of medication with psychosocial therapy appears to be the best option for treating opioid abuse; the usefulness of psychosocial treatments, such as talk therapy, on their own remains unclear. Next, naloxone has developed into an effective frontline response to opioid overdose. In the 15 years following its approval in 1996, the CDC estimates that over ten thousand overdoses were reversed via naloxone administration. It’s also important to remember that doctors’ offices represent some of the most common portals for opioids to enter the population, and evidence suggests that federal oversight can effectively reduce the number of prescriptions that doctors write. Lastly, any successful treatment plan must take a long-term approach as opposed to “quick fixes.” All of these efforts will benefit if addiction is studied and treated like the deadly disease that it is.

We The People – The Political Response

New Hampshire’s status as a both a swing state and early primary state has played a significant role in bringing the conversation about opioids into the political sphere. The opioid crisis has hit the Granite State particularly hard, sending its per-capita rate of overdose deaths soaring to one of the highest in the nation. As a result, presidential candidates and lawmakers all over the country have begun to discuss anti-abuse policies with newfound fervor.

On a federal level, addressing the opioid crisis appears to be one of the few issues that garners bipartisan support…at least on the surface. After President Obama called for $1.1 billion in additional funding earlier this year, Congress overwhelmingly passed the Comprehensive Addiction & Recovery Act (CARA), which is the first major piece of addiction legislation in decades.

While many of CARA’s measures support tried-and-true strategies for treating addiction—including several mentioned in this article—partisan wrangling dulled their likely impact. In particular, CARA doesn’t include any direct funding, opting instead to merely authorize the spending increase and rely upon Congress to earmark funds for next year’s federal budget. It also left some of its most effective programs, such as oversight of doctors’ prescribing practices, as voluntary. On a brighter note, CARA supports additional research into the treatment of both pain and addiction.

In stark contrast to the federal government, many states have already delivered aggressive policies. For example, New York passed sweeping legislation in June that increases patient access to naloxone, mandates addiction and pain management training to medical professionals, and dramatically lowers barriers to comprehensive treatment plans. Similarly, Minnesota’s legislature expanded statewide access to naloxone back in 2014 and its police officers have focused on providing educational resources to local communities.

An encouraging amount of new addiction legislation has eschewed simple or “miracle drug” solutions for scientific, evidence-based approaches. The opioid crisis is oozing its way through the cracks formed by outmoded thinking, and it will continue to do so if government officials don’t act. Saying that this fledging round of policy decisions will impact millions of lives isn’t hyperbole. It’s reality.

Christopher Gerry is a third-year graduate student in the Department of Chemistry and Chemical Biology at Harvard University.


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3 thoughts on “Drugs, data, and public policy: What can science teach lawmakers about the opioid crisis?

  1. It’s amazing the amount they invest in opiate research, and combating addiction and deaths from opiates. Then when the one natural herbal solution (kratom) starts to make headway, and changing people’s lives in a positive way, the DEA steps in and attempts to label it schedule 1, same class as cocaine or lsd.
    Kids may laugh at you in school for having to ride the short bus, but you’ll show them when you grow up and get a high paying government job.

  2. I have had to take low level opioids for headaches associated with hydrocephalus, and now an autoimmune (likely sarcoidosis) disorder who’s pain dwarfs my hydrocephalus. I’m not a big fan of hydrocodone, and now the government’s new restrictions frustrates me further. I am also a neuroscientist, so I understand the mechanisms of addiction. And I am a big believer and personal user of a number of the integrative arts & therapies. I think we could agree that one distinguishing factor in health care in the U.S. versus Europe is in the use & coverage of integrative arts. And I must ask with so much data on opioid addiction, why isn’t there more utilization of integrative therapies, and why isn’t there a patient profile test to determine the likely long & short term effectiveness & risks of the various pain meds & modalities? This would seem it could help predict how specific patients would respond to specific pain management regimens. I can’t help but think that limited insurance reimbursement of integrative therapies, the financial interests of drug co’s, and government agencies looking to expand the scope of their authority — all play a significant role in this crisis. And this needs to be addressed.

  3. Overall, I think you nicely put everything together. I do want to point out that oral methadone is not slowly released into the blood stream. Onset is 0.5 to 1 hour, it takes about 1 – 7.5 hour for the blood to have a peak concentration. The reason why methadone is used for opioid addiction is its long elimination half-life, 8 – 59 hours for adults. Most patients with a daily dose can maintain a stable blood concentration which helps them overcome cravings.

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