The worst risk of opioids, obviously, is overdose, whether intentional or not. An astonishingly elegant, simple, and apparently effective idea is now emerging to safeguard against this: Give pain patients taking opioids a supply of naloxone, an opioid antagonist, to have on hand at home in case of overdose.
Naloxone (Narcan) is a standby in emergency rooms. In fact, drug addicts who overdose are routinely injected with naloxone to reverse potentially fatal breathing problems. Naloxone is also available as a nasal spray. In both forms, naloxone rapidly knocks heroin and other opioids off opioid receptors, potentially triggering instant withdrawal but also restoring breathing and thus saving lives. It has virtually no abuse potential and a favorable safety profile.1 In the harm-reduction scenario researchers are now exploring, pain patients would simply get a prescription for naloxone from their doctors along with their opioid prescription. Naloxone is not a controlled substance and hence could be prescribed by any doctor and many advanced practice nurses. Better yet, some say, given its good safety profile, naloxone could be made available over-the-counter.2
In Wilkes County, North Carolina, in a community-based effort called the Lazarus Project, free, intranasal naloxone has been central to successful efforts to combat opioid overdose deaths.3 Preliminary data, published in 2011 in Pain Medicine, show that, though Wilkes County initially had one of the highest drug overdose death rates in the nation, the Lazarus Project was linked to a reduction in deaths from 46.6 per 100,000 in 2009 to 29.0 per 100,000 in 2010.4 The Lazarus Project involved both substance abusers and pain patients. (Pain patients on long-term opioids are actually less likely than substance abusers to develop respiratory depression because they often become tolerant to the drugs.5)
In Boston, Massachusetts, the city’s public health commission reported in April 2011 that deaths from overdoses among abusers of heroin and other opioids plunged after the city began distributing Narcan kits to addicts in 2006.6 Overdose deaths dropped by 32 percent between 2007 and 2008 alone, the city said. The success of the Boston program has spurred Massachusetts to begin a larger, statewide program to distribute Narcan in hopes of reducing overdose deaths.7 When sprayed into the nose, Narcan is “safe, easy to administer and has no potential for abuse,” the state says.
At the national level, the federal Centers for Disease Control and Prevention announced in February 2012 that community-based programs using naloxone have prevented the opioid overdose deaths of 10,171 people since 1996. As of October 2010, there were at least 188 such programs in the United States, the agency said.8 Perhaps in part because of that success, the US Food and Drug Administration is now considering approval of wider distribution and use of naloxone.9 While both the injectable and nasal spray forms of naloxone work well, a big advantage of the nasal formulation is that rescuers don’t need to draw up naloxone in a needle and inject it, says anesthesiologist Daniel Carr of Tufts University.10 Using a nasal spray also eliminates the potential problem of infections from needles.
But there is an obvious drawback to the naloxone “rescue” idea. For it to prevent death in someone who has overdosed, there must be other people around—friends, relatives, or emergency medical personnel—who recognize when someone is in trouble and know how to administer naloxone.
In addition to preventing deaths from opioid overdoses, doctors and scientists are trying to find ways to help people in pain who become physically dependent on or even addicted to opioids to withdraw from them safely. This can get tricky. While on opioids, a person may think he or she is no longer in pain. But if the pain is still present, it may get worse again if the opioids are decreased or stopped, making it a delicate balancing act to manage the symptoms of opioid withdrawal while controlling the pain. It’s more still difficult still to treat chronic pain in people who also have a history of substance abuse.
Understandably, many pain patients want nothing more than to get off opioids the minute they think their pain is better. If drugs are the problem, the thinking goes, why not just get all that bad stuff out of your system as fast as possible, hope that the underlying pain is really gone, and get on with life? And it often is that easy. “Tens of millions of people per year are started on some dosage of opioids and all pretty much get off. As the need diminishes, they just taper the dose. It happens all the time and people don’t think about it,” Carr of Tufts told me.11 This is especially true for people taking opioids for a few weeks or so after surgery.
But as we saw with Paul Konowitz, the Boston physician and pain patient we met in Chapter 7, getting off opioids can sometimes be more difficult, in part because many doctors don’t know how to help people do it. The simplest way, says Carr, is to taper very, very slowly, cutting the dose of opioids by about 10 percent a week. “That’s super gentle,” he said, and usually avoids symptoms of withdrawal, also known as opioid abstinence syndrome.
Some people, very eager to get off drugs, don’t do it quite that slowly. Keosha Johnson, an editor/producer at WBUR.org in Boston was one of them.12 After spinal fusion surgery, she was discharged from the hospital and told to take oxycodone, which worked very well to control her pain. In fact, it made her feel normal. About six weeks later, she decided she didn’t need it anymore. “I did know I was supposed to taper off,” she says. “I was told that when I was in the hospital, and given paperwork that said to call my doctor when I was ready to get off to get specific instructions on how to do it. I just forgot. Plus, I figured I could quit cold turkey because I was no longer in pain—it never occurred to me that I would experience severe withdrawal after taking it for six weeks.”
But she did. Within a day of taking her last dose, she lay in bed “practically twitching, as an intense jittery feeling spread through my upper torso. I tossed and turned until dawn, breaking a sweat as I repeatedly stretched one arm, then the other, as something akin to having consumed several cans of Red Bull continued to wreak an internal havoc inside of me.” She called her doctor, who told her to taper more slowly, which she did, with few problems. Now she is opioid-free.
For people who do encounter opioid withdrawal symptoms, it’s reasonable to counteract those symptoms with judicious use of other drugs, Carr says. Granted, it may sound crazy to think of taking more drugs to combat the effects of the initial drugs. But done properly, it can be a safe, temporary fix to allow the body to get its biochemistry back to normal. One drug that can ease the agitation of opioid withdrawal is clonidine, a blood pressure medication that reduces the jittery feelings that are triggered when the body overproduces the stress hormones epinephrine and norepinephrine during opioid withdrawal. Clonidine also blocks excessive epinephrine and norepinephrine production. Another option is a sedating antidepressant medication such as Trazodone, which blunts the tendency of the heart to race and blocks some of the agitation and anxiety triggered by withdrawal. If opioid withdrawal triggers intense anxiety, benzodiazepines such as Ativan can also help. (Dependence and addiction can be a problem with Ativan, but to a lesser extent than with some other drugs.13) Antiemetics can also be used to combat nausea and vomiting, antidiarrheals to treat diarrhea, and quinine to help with skeletal muscle cramps.14
The reason it can be hard to get off opioids is that once you have been taking them regularly, opioid receptors in the nervous system get used to being occupied. And they don’t like it when they’re suddenly empty. If you stop cold turkey, opioid receptors start “screaming because they are no longer full. You get pain, sweating, chills, abdominal cramps, muscle aches. That’s where the expression ‘kicking the habit’ came from—people kick their legs to relieve the muscle cramps,” explains Carol Garner, an addiction specialist at Boston’s Faulkner Hospital.15 That’s why tapering very, very slowly is key.
But what if you have become, not just physically dependent on opioids, but addicted? And what if, in addition, you still have a legitimate problem with chronic pain? What if, in other words, you are both a pain patient and a person with addiction? This is a difficult problem for patients and doctors alike, but even here, there are options.
One is methadone, a substitute opioid that can be used as a maintenance drug. That is, it fills up opioid receptors to reduce symptoms of withdrawal from and craving for other opioids while also providing pain control.16 Instead of needing an opioid every three to six hours, a person can take methadone once a day and still avoid withdrawal symptoms, says Jan Kauffman, an addiction specialist at the North Charles Institute for the Addictions in Somerville, Massachusetts.17
When used primarily for pain, as opposed to addiction, methadone is often given two or three times a day.18 It can be taken for years if necessary. Another benefit of methadone is that it can be taken orally instead of by injection. As long as a person stays on methadone, it reduces the risk of addictive behaviors like injecting drugs, which can lead to more problems, including AIDS and hepatitis from dirty needles.19, 20, 21
A possibly better, though more expensive, option for pain patients who have become addicted to opioids may be buprenorphine, which is also an opioid, but one that binds to some opioid receptors less strongly than other opioids.22 (Buprenorphine is sold as Suboxone and Subutex. Pure buprenorphine is Subutex; if the opioid blocker naloxone is added, it’s Suboxone.)
When an opioid hits its receptor, the receptor changes its physical shape, which triggers a cascade of chemical events inside the cell that, ultimately, leads to pain relief. But tiny changes in the shape of an opioid can make it fit more or less securely into the receptor. Morphine, for instance, binds very well to opioid receptors or, to put it more technically, has a high “affinity” for these receptors. Buprenorphine keeps opioid receptors occupied, but not fully.23 In theory, buprenorphine binds just enough to keep withdrawal symptoms away, and to provide some pain relief as well. Often, for someone who has both persistent pain and addiction, a doctor trained in both pain and addiction medicine will “cross-taper” regular opioids and buprenorphine. It’s a pretty complicated regimen,24 but involves slowly decreasing the dose of the standard opioid and gradually increasing the dose of buprenorphine.
Buprenorphine doesn’t seem to have the same overdose risk of other opioids, and also appears less likely to produce respiratory depression and tolerance. (Tolerance means a person needs more and more of a drug to achieve the desired effect.25, 26) In the buprenorphine-plus-naloxone formulation, there’s also a built-in anti-abuse feature. If someone tries to crush the tablets, mix the powder with water, and inject it to get high, the naloxone will kick in and block the effects of buprenorphine, triggering withdrawal.
In 2011, researchers at McLean Hospital and Harvard Medical School conducted the first randomized large-scale clinical trial at 10 sites nationwide with 653 people who were physically dependent on prescription opioids. Almost half were people who also had chronic pain. The researchers tested the effectiveness of Suboxone for different amounts of time and with different amounts of counseling added.27 Short-term Suboxone treatment did almost no good—only about 7 percent of patients randomized to a two-week treatment followed by a two-week tapering off period were able to get off and stay off their prescription opioids. In the group that took Suboxone for 12 weeks, followed by a four-week taper, however, almost half the group (49 percent) successfully got off prescription pain relievers. (The group that had the longer treatment were those who had failed with the shorter treatment.) The amount of counseling made no difference in outcomes. But here’s the bad news: Once Suboxone treatment was stopped, there was a high rate of relapse.
Buprenorphine can also be used under the tongue, transdermally (through a patch on the skin),28 and via implants. In a study led by researchers from the University of California, Los Angeles, doctors at 18 medical centers around the country studied people with opioid dependence recruited from addiction centers. They randomized the patients to get implants of buprenorphine or implants of a placebo medication. (The study did not include people with chronic pain requiring opioid treatment.) All were followed for six months, and they provided regular urine samples as they went along. The results were impressive. The buprenorphine group had significantly more “clean” urine samples, meaning they had not taken illicit drugs, during the study than the placebo group. The buprenorphine group also had fewer withdrawal symptoms and less drug craving.29 If confirmed by further studies, the new findings would represent a major advance.30
Implantable buprenorphine has the additional advantage that once it’s placed under the skin, it can’t be tampered with, so it is less likely than an oral formulation to be abused. A study of transdermal buprenorphine in 1,160 people, this time, in people with chronic back pain, also yielded encouraging results.31 On the downside, taking buprenorphine is no walk in the park. It can cause nausea, vomiting, constipation, headaches, leg swelling, and insomnia.32
Methadone and buprenorphine are not the only drugs used to treat opioid dependence and addiction. In 2010, the FDA approved an extended-release form of naltrexone (marketed as Vivitrol), which acts by blocking opioid receptors but is not itself an opioid, as buprenorphine is. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, praised Vivitrol’s approval as “a significant advancement.”33
Opioid rotation is another approach to managing opioid problems, particularly tolerance and opioid side effects. One of the leaders in modern opioid rotation is Perry Fine, a pain specialist in Salt Lake City, Utah. Fine grew up wanting to be a professional cellist and composer, became “addicted” to soccer while going to high school in France, then swerved to science and finally medicine, because, he said smiling, he wanted “to be of service and have a meaningful life.”34
He certainly has had that. When the Olympics took over Salt Lake City in 2002, Fine, who had been the sideline trauma physician for the University of Utah football team, was there at the ice center, watching Sarah Hughes win the gold in figure skating and tending to the other athletes’ aches and pains. But his real passion has become helping people in chronic pain and teaching doctors how to use opioids more safely and effectively. To that end, Fine, along with Russell Portenoy, the New York pain specialist, Roger Chou, a pain specialist at the Oregon Health & Science University and a handful of others, have fine-tuned a systematic way of rotating opioids to minimize tolerance—the body’s adaptation to opioids that results in needing higher doses to get the same reduction in pain. The idea is to rotate opioids without triggering new bouts of pain.
Opioid rotation formulas have been around for 40 years and are slowly being revised as pain specialists learn more about the drugs.35, 36, 37, 38 The goal, says Fine, is to use “equianalgesic tables” to estimate what dose of the opioid to be tried is equal in pain relieving capacity to the old one that is no longer working or that has too many side effects. This is stated in morphine equivalents. In other words, the prescribing doctor mathematically calculates the daily dose of the old opioid as an equivalent dose of morphine, then uses the tables again to convert from morphine to the new opioid; the doctor then reduces the dose of the new drug slightly to avoid overmedication. Ideally, the doctor does a second assessment soon after the patient changes to the new drug, and lowers or raises the dose accordingly. The patient’s job is to be alert to increases or decreases in pain and side effects. It sounds easy. But in practice it becomes very tricky, partly because each person responds differently to any given drug. Certain drugs (especially fentanyl and methadone) are especially complex. Things also get complicated changing from an oral drug to an IV formulation or from long-acting to short-acting, or vice versa.
In fact, one of the biggest problems in opioid rotation is prescriber mistakes, which can occur because of insufficient training and the use of inaccurate dose conversion tables, conclude Fine and Utah colleague Lynn Webster, medical director of Lifetree Clinical Research in Salt Lake City. In 2012 papers,39, 40 Webster and Fine describe a new paradigm for a patient who needed to be changed from extended-release oxycodone to extended-release hydromorphone. They slowly decreased the oxycodone while slowly increasing the hydromorphone. The key was to provide enough fairly fast-acting rescue opioid to handle breakthrough pain and stop acute withdrawal symptoms. Webster’s and Fine’s technique involves three steps—reducing the original opioid dose by 10 to 30 percent while starting the new opioid at the lowest available dose, then further reducing the original opioid by 10 to 25 percent per week while increasing the new opioid by 10 to 20 percent. All the while, it’s important for the patient to use rescue opioids occasionally as needed if pain becomes too intense. Most patients can be rotated safety to the new opioid in about a month. But it takes a careful doctor and a careful patient to keep track of three different medications (the old opioid, the new one, and the rescue drug) on a specific schedule.41
One of the holy grails for researchers has been to create versions of opioids that are harder to abuse—so-called abuse-deterrent, tamper-resistant, or tamper deterrent formulations of existing drugs.42, 43 These are drugs that are designed to be harder to tamper with or to use improperly, such as by crushing the drugs in order to snort or inject them. (Obviously, determined abusers can still swallow abuse-deterrent drugs in excessive quantities to get high.)
Importantly, the abuse-deterrent formulations are made with abusers, rather than responsible pain patients, in mind. But these drugs can indirectly help pain patients if they reduce abuse and the resulting stigma attached to opioids.
Abuse, of course, can happen with both long-acting and short-acting oral opioids. But long-acting opioids are particularly worrying because, if abusers crush or chew them, they get the full dose of the opioid all at once, not, as is supposed to happen, over many hours. At high enough doses, this form of abuse can be fatal.44
In August 2010, Purdue Pharma began selling an abuse-deterrent formulation of OxyContin that is harder to crush. (In Canada, it’s sold as OxyNeo, according to Purdue spokesman Jim Heins.45) The new version breaks into chunks rather than a powder, as Katherine Eban explains in 2011 in Fortune.46 If water is added, “the result is a gelatinous goop. So far, the new OxyContin appears to be withstanding attempts to crush, snort or inject it.”
Which is precisely the deterrent effect the manufacturer hoped for. The street price of the abuse-deterrent formulation—the price abusers are willing to pay on the black market—has dropped from 73 cents per milligram to 52 cents, Eban reported. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System, a program funded by Purdue, also show that abusers, as hoped, do not like the new OxyContin.47, 48, 49
But there’s downside to this apparent success. Early signs show that determined abusers are switching to other opioids, including heroin. In a July 2012 letter to the New England Journal of Medicine, researchers from Washington University reported that the percent of drug abusers who chose OxyContin as their primary drug of abuse dropped from 36 percent before the release of the new abuse-deterrent formulation to 13 percent today. In the same time period, abusers reported that their use of heroin almost doubled.50, 51 Besides OxyContin, other harder-to-crush opioids are now on the market, including Exalgo (by Covidien), Opana ER (by Endo), and Nucynta ER (by Janssen). It’s too soon to tell what the abuse-deterrent effect of these formulations will be. But abusers who are now shying away from OxyContin do seem to be turning to Opana as well as heroin.52
Coming up with strategies for abuse-deterrent opioids has not been easy, and some seemingly good ideas have fallen by the wayside. One idea was the cleverly designed Embeda, an extended-release combination of morphine and naltrexone. Morphine was placed around the outside of the pill, with naltrexone, an opioid blocker, sequestered on the inside. If you swallowed the pill as intended, you would get the long-lasting, pain-relieving effects of morphine; the naltrexone would not be absorbed and would just pass right through your system, doing nothing. If, however, you crushed or chewed Embeda, the naltrexone would be released all of a sudden, which would keep the morphine from binding to opioid receptors. This would prevent a high, and would also bring on sudden, potentially dangerous, withdrawal, making the drug decidedly unattractive to abusers. Unfortunately, safety problems temporarily doomed Embeda and in March 2011, King Pharmaceuticals recalled all dosages of it.53
Drug makers have tried other abuse-deterrent strategies—like adding something noxious to opioids such as niacin, a vitamin that, in high doses, produces uncomfortable flushing. A potential drug in this category was Acurox, oxycodone plus niacin. But the FDA rejected it on the grounds that niacin was not a powerful enough deterrent.54 The agency also rejected another abuse-deterrent product, Remoxy.55 Currently, researchers are also testing other ways to reduce abuse. One strategy is to create prodrugs that become active only when the body metabolizes them. The chemical process of metabolism converts the opioid from an inactive to an active form.56 Still another idea is an anti-opioid vaccine, which, in theory, could protect against both heroin and HIV. Pieces of the heroin molecule would be attached to the tetanus bacterium to stimulate antibodies against heroin. So far, it has not been tested in the real world, but is being studied at the Walter Reed Army Institute of Technology, sponsored by the National Institute on Drug Abuse.57
Increasingly, pain specialists are requiring patients to sign contracts, or the term many pain specialists prefer, agreements, which spell out the opioid doses to be taken, the risks of misusing the drugs, a list of rules and obligations, and signs of side effects and potential improvement to be recorded.
It sounds reasonable. But some analysts and ethicists worry that the contracts can be insulting and stigmatizing for patients. After all, we don’t force people with other medical problems to sign such things. The agreements may be a decent educational tool for informing patients about the risks and benefits of opioids. There’s certainly no harm in making sure people understand the risks and benefits of any drugs they’re taking, opioids included. And there’s no harm in reminding people not to try to refill prescriptions too early, not to increase doses on their own, and not to drink alcohol with medications.
The trouble is, it’s not clear how effective such documents really are. Moreover, they can potentially do more harm than good by interfering with the essential trust between patient and doctor. Some agreements actually border on the offensive, like those that say, “You will be on time for appointments,” or “You will be respectful to me and my staff.”58 (As far as I know, agreements don’t specify that doctors be on time or be respectful toward patients.) More important, medication agreements often miss the point. What pain patients really want from their doctors is pain relief, not a discussion of the public health problems of opioid misuse. In other words, contracts essentially shift the locus of concern from helping pain patients to protecting providers against the perceived risk from regulatory and law enforcement agencies, says Myra Christopher of the Kansas City–based Center for Practical Bioethics. In essence, she says, medication contracts address a social problem—the drug abuse epidemic—rather than a clinical problem, as if every pain patient were a potential criminal.
In a paper in 2010, Christopher and a team of leading ethicists and pain specialists argue that contracts don’t really address the problem of opioid drug diversion. As federal statistics show, the main way opioids get into the wrong hands is not by bad patients trying to scam their doctors but from friends and family—including home medicine cabinets from which opioids can easily be taken. Intentional diversion by patients, the Christopher team notes, is potentially quite small. Compelling patients to sign medication agreements, in other words, not only focuses on a comparatively trivial part of the diversion problem, but it stigmatizes patients and corrodes patient–doctor trust.59
A much better approach, the bioethicists say, is to use standard informed consent forms that spell out potential risks, as is done for surgical procedures. Some major medical organizations—including the American Academy of Pain Medicine and the Veterans’ Health Administration, as well as the Federation of State Medical Boards—do say that physicians should consider medication contracts for patients at high risk for medication abuse on the grounds that such contracts may be helpful for patients having difficulty managing their medications. But curiously, when the US Food and Drug Administration in 2009 first introduced its idea for a different drug-control program (REMS, which we’ll get to in a minute), it endorsed these “prescriber–patient agreements.” But in June 2010, after public hearings, the FDA issued its final recommendations for REMS and no longer required the universal use of opioid contracts or agreements.60
In any case, it’s not clear how effective medication agreements are. The research is ambiguous.61 A 2010 review by researchers from New York, Boston, New Haven, and Philadelphia, for instance, looked at 11 studies and found only relatively weak evidence supporting the use of patient contracts along with urine testing.62 And there are potential harms. The New York team, led by Joanna Starrels of Albert Einstein College of Medicine, worried that patients might feel so stigmatized by the contracts that they might forgo pain treatment. On the other hand, some respected pain specialists, like Harvard Medical School’s Robert Jamison, think the contracts are valuable if they encourage communication between the patient and the doctor, and reinforce to patients that they should not “doctor shop” or use up their pills faster than prescribed. But they’re certainly not a panacea, he adds, because “folks who misuse [drugs] will agree to anything.”63
Medication contracts may clarify patient and physician responsibilities, noted California public health guru Mitchell Katz. “But when you create a contract, and the patients do not follow their part of the bargain, what do you do next?”64
The contracts may also be unenforceable for a number of reasons, writes commentator Mark Collen in the Journal of Law, Medicine & Ethics.65 An opioid contract, he says, may be considered an “unconscionable adhesion contract,” which means it is, in essence, a contract prepared by one party (a doctor) to be signed by a party (the patient) in a weaker position. Given the asymmetrical power distribution in the doctor–patient relationship, such a contract may be intrinsically unfair because it does not involve meaningful choice for the patient. And there’s one last concern: Opioid contracts are often written at such a high level as to not be fully understood by the patient.
* * *
Another tactic to try to make sure pain patients don’t abuse opioids is urine testing. Indeed, many opioid contracts stipulate that patients must submit to random urine drug testing, to see whether people are taking the right medications and not mixing them with other drugs. The CDC recommends such testing for any patient younger than 65 with non-cancer pain who has been on opioids for more than six weeks.66 The influential Federation of State Medical Boards also thinks they can be helpful in people at high risk for medication abuse.67 A panel of experts convened to write opioid prescribing guidelines also recommends periodic urine testing, or some other monitoring information, for patients at high risk for abuse.68
But once again, we have to ask: Does urine testing yield clinically meaningful results? Is it overly stigmatizing? Who is it really protecting? Who really benefits, besides urine testing companies? And how reliable can it be when patients can buy “clean” urine on the Internet?69
There’s another question, too: Is urine testing even constitutional? Randomly testing people simply because they seek treatment with opioids for chronic pain could, arguably, be considered a “suspicionless and warrantless search” that could violate both the Fourth and Fourteenth Amendments.70 To be sure, it may make some patients feel secure to have urine tests that monitor medication levels or detect whether patients are mixing drugs inappropriately. But urine testing also may send a patient the message that the doctor does not trust him or her—an appropriate message for some people, but insulting and demeaning for others. (There’s also some evidence that urine testing can be racially discriminatory, according to a Yale University study involving 1,612 patients.71)
What is clear is that a sizable chunk of pain patients on opioids who take urine tests flunk. In a 2007 Harvard study, 45 percent of 470 patients had abnormal urine tests—a red flag for what’s awkwardly called “aberrant drug-related behaviors,” to be sure.72 And that’s not too surprising. Many people do not take their medications in the specific ways their doctors prescribe. A national survey of 76,000 urine tests for prescription drug medications by Quest Diagnostics, a testing company, showed that 63 percent of patients take their medications in ways inconsistent with their doctors’ orders—including missing doses and combining medications.73, 74, 75
But even with something as seemingly objective as urine testing, it’s impossible to come to definitive conclusions.76 Some tests may also have built-in validity problems, in part because some drugs leave the body much more quickly than others.77 This, of course, makes the timing of urine drug testing tricky. In other words, urine tests may only show a short snapshot in time and reveal nothing about longer term drug use or abuse.
It’s also troubling that some studies that purport to show the effectiveness of urine testing are paid for by companies that make the urine tests. The profit motive, rather than public health, may be spurring the growing use of testing.78 Indeed, some published studies claiming to show the value of urine drug testing are written by employees of or contractors from drug testing companies.79, 80 A presentation on urine drug testing at the 2012 annual meeting of the American Academy of Pain Medicine, for instance, was sponsored by Ameritox, a drug test lab.81, 82 But Ameritox has a troubled reputation. In 2011, Ameritox was forced to pay $16.3 million to the federal government to settle claims that it provided kickbacks to physicians for drug testing.83, 84, 85 In June 2012, Ameritox and a competitor, Millennium, did battle in court over what Millennium alleged were false and deceptive advertising claims by Ameritox. (The court agreed, but did not assess monetary damages.86, 87)
Urine drug testing also has cost considerations for pain patients. If office-based urine testing proves inconclusive, patients may have to pay out of pocket for additional, outside testing.88
Finally, for people in pain who find themselves subject to urine testing, there are some clear dos and don’ts. For example, don’t eat a poppy seed bagel (or anything else with poppy seeds) before a urine test— the test might show morphine or its metabolites;89, 90 and do be up front with your doctor—before any urine test—about all medications, legal and illegal, that you take, including dietary supplements. If you’ve been at a party where there was marijuana smoke, mention that, too, even if you didn’t actually smoke yourself. Telling your doctor about everything you’re taking is good for your own health and safety. And fessing up ahead of time preserves your credibility.
Among the most important strategies for combating opioid abuse and diversion are prescription monitoring programs (PMPs), also called prescription drug monitoring programs (PDMPs). In different forms, these state-based programs have been around for decades. Today, almost all states now either have PMPs in place or have enacted legislation to set up such programs.91, 92, 93, 94, 95 Not surprisingly, the PMPs vary considerably state by state.96
In general, the goal of these state programs, which are funded in part by the federal Department of Justice and the Department of Health and Human Services, is to collect dispensing data in order to detect questionable patterns of drug use, such as “doctor shopping” or “pharmacy shopping,” and thereby—in theory—reduce diversion of opioids.97
The data collected by PMPs are available, depending on specific state-by-state laws, to a lot of people—physicians and other practitioners; pharmacists; federal, state, and local law enforcement personnel; professional or occupational licensing authorities; and individuals whose receipt of prescriptions has been included in the PMP database.98 This raises potential confidentiality concerns, although typically law enforcement personnel must show that they have probable cause— good reason—to be interested in the information. Just as troubling, there is no clear evidence that PMPs are either safe or effective—with safety, in this case, meaning doing no harm (such as reducing access to opioids by pain patients) and effectiveness meaning catching people who really are out to abuse or divert the drugs.
PMPs get dispensing data from pharmacies, then make them available to law enforcement agencies and prescribers. (How much access to this data law enforcement should have and under what circumstances are major points of contention.) The programs typically require pharmacies to put prescription data into a centralized, electronic database, including information that identifies the prescriber, dispenser, and patient, along with the drug, dosage, and amount dispensed.99 In theory, PMPs could be the basis for a reasonably balanced opioid policy that would allow legitimate pain patients access to the opioids they need while restricting access to abusers, says June Dahl, a professor of neuroscience at the University of Wisconsin who is widely regarded as a leader in opioid policy research. “If we had effective PMPs,” she told me, “we wouldn’t have to be thinking about other federal mandates, which have great potential to adversely affect quality of care.”100
But it’s unclear how useful PMPs are.101 A 2002 General Accounting Office review looked at PMPs in 15 states and found that PMPs did seem to reduce the time and effort needed by regulatory bodies to investigate drug diversion cases.102 But the report also revealed a problem: States that border a state with a PMP often had an increase in the supply of prescription drugs, suggesting that patients went “doctor shopping” to get their drugs. In 2006, researchers for the federal Department of Justice reviewed the evidence on PMPs and concluded that when PMPs share their data readily with prescribing physicians and pharmacists, there is a 10 percent drop in prescription sales and a reduction in prescription drug abuse.103 But this drop in prescriptions could mean more under-treatment of pain for legitimate patients. In a 2010 study, Boston-area pain specialist Nathaniel Katz focused on one state—Massachusetts— and tracked 11 years’ worth of PMP data, from 1996 to 2006.104 He found that it was only when people used four or more prescribers or got their drugs from four or more pharmacies that there were signs of questionable activity.
At best, PMPs address the problem of drug diversion stemming only from prescribing relationships, not the larger issue—getting drugs from family, friends, and unlocked medicine cabinets.105 Moreover, many doctors don’t even know about PMPs, which means that even well-intended state efforts are seriously underutilized. Prescription drug monitoring programs can also be cumbersome and expensive, as the state of California has discovered.106
One of the researchers concerned about the efficacy of PMPs is psychologist Robert Twillman, director of policy and advocacy at the American Academy of Pain Management, who thinks the programs do work, though that hasn’t been scientifically shown yet.107, 108 His findings are discouraging. He compared states with and without programs using data from a single year, 2003. In general, he found that in states with PMPs, there is a reduction in prescriptions for some opioids, but there’s a concurrent increase in others such as Vicodin. While PMPs may trigger a shift in the pattern of prescribing, actual rates of abuse may not drop at all.109 Moreover, even if a state with a PMP experiences a sudden drop in prescriptions, it’s hard to know what that means. Does it mean less abuse and diversion? Or does it mean that doctors are getting even more scared of writing pain-reliever prescriptions?
In other words, while in theory PMPs should help control abuse and diversion, there’s not much research to support that. The programs may indeed identify people who “doctor shop” and “pharmacy shop,” but even doctor shopping and pharmacy shopping may simply indicate that pain patients are having trouble getting the help they need. PMPs may also create an unintended substitution effect, whereby doctors, fearful of getting ensnared in PMP red tape, write fewer prescriptions for some drugs and more for others that may not be as effective for chronic pain. Most important, PMPs may not accomplish a most basic goal—lowering the rates of overdose and death from opioids.
The most troubling—and controversial—assessment of PMPs came in 2011 from the government itself, specifically, the federal Centers for Disease Control and Prevention (CDC). It conducted the first major study assessing the effectiveness of PMPs, examining data from 1999 to 2005 across the United States. The study was flawed. PMP efforts in different states were set up so differently that comparisons were not easy. In some states, PMPs were just getting started. And federal funding to assist states in their PMP efforts kicked in only partway through the study.110
Nonetheless, the CDC study is provocative. It found that PMPs were not significantly associated with lower rates of drug overdose or opioid overdose mortality or lower rates of consumption of opioid drugs.111 In fact, the effect of PMPs on overall consumption of opioids appears to be minimal. On the other hand, a 2012 study that looked at information from two drug abuse surveillance databases showed more encouraging results.112 The analysis supports the idea that PMPs are associated with a mitigation of increasing opioid abuse and misuse over time in both the general population and in people seeking help at opioid treatment centers.
The potential downside of PMPs for pain patients remains a concern for pain patient advocates like Cindy Steinberg, the woman we met in Chapter 1 who has been in constant pain since office filing cabinets fell on her back nearly 20 years ago. Steinberg has devoted most of her life since the accident to the nonprofit Massachusetts Pain Initiative. She worries that with enhanced PMPs, prescribers may be targeted inappropriately for investigation.113 And that pain patients who get prescriptions from more than one provider may be unnecessarily stigmatized and denied needed medication.
As I discovered in my own pain journey, legitimate pain patients often do see different specialists in the quest for better treatment, and many or all of these specialists may write prescriptions for pain medications. Instead of casting suspicion on all patients who get prescriptions from more than one provider, perhaps a fairer standard would be to raise red flags only on those who get pain medications from, say, more than four practitioners and visit more than four pharmacies.
Chances are, you’ve never heard of REMS, except in the context of rapid eye movement sleep. It’s a bureaucratic term for a plan now required by the US Food and Drug Administration.
In 2007, the Food and Drug Administration Amendments Act gave the FDA the authority to require an opioid risk evaluation and mitigation strategy (REMS) from manufacturers, the idea being to reduce diversion, abuse, misuse, and overdose.114, 115, 116 In April 2011, after considerable back-and-forth between the federal bureaucracy and industry, the FDA formally announced it would require REMs for extended-release and long-acting opioids,117, 118, 119 and reiterated its position that opioid REMS would not be unduly burdensome on patient access.120
The REMS approach, finalized in July 2012, is a start—requiring that industry be more forthcoming about the risks of various drugs and that companies provide detailed educational materials about the drugs to providers. Under the program, manufacturers must pay for the development and implementation of the drug education materials by third-party providers.121 It’s not clear yet, however, what these educational materials would contain; they could contain language—for instance, suggested limits on daily doses of morphine—that could be detrimental to pain patients.122 Moreover, do we really want the pharmaceutical industry to produce these educational materials? The industry has a vested interest in what might be called “creative risk/benefit messaging.”123
The finalized REMS program applies to all extended-release (ER) and long-acting (LA) opioid analgesics, including, but not limited to, fentanyl, hydromorphone, morphine, oxycodone, and oxymorphone and is expected to affect more than 20 manufacturers.124, 125 The impact could be huge. There were an estimated 22.9 million prescriptions for extended-release and long-acting opioids dispensed in 2011, according to industry tracking data cited by the FDA. More than 320,000 prescribers registered with the Drug Enforcement Administration wrote at least one prescription for these drugs in 2011.126 Importantly, REMS do not make it mandatory that providers actually take the courses or use the educational materials in order to prescribe the extended-release or long-acting opioid drugs to patients. The Obama administration does want a mandatory training program on opioid prescribing that would be linked to DEA registration by providers, but such a program would require legislation that has not yet been approved.127
There’s concern among patient advocates that REMS might limit access to opioids for pain patients by making doctors less likely to prescribe them, despite the FDA’s insistence to the contrary.128
And the FDA’s focus on long-acting medications could mean that doctors might switch to shorter-acting opioids like Percocet, Vicodin, and Tylenol #3, which can be less effective at pain relief and harder for patients to titrate.129 (The oxycodone in Percocet and the hydrocodone in Vicodin, for instance, are effective pain relievers, but the doses are limited by the acetaminophen also contained in these medications.130)
For what it’s worth, industry seems amenable to the REMS program. “We embrace risk management,” said Herbert Neuman, vice president of medical affairs at Covidien (which makes Exalgo). “The problems of overdose, abuse and death have to be worked on by everybody. Manufacturers have to be part of the solution as well.”131
Government programs aside, there are ways to use opioids more safely. In fact, a number of guidelines exist for safe opioid prescribing. In general, they say that physicians should assess patients carefully for potential opioid abuse; assess and treat co-occurring mental health problems such as anxiety and depression; use published tables for converting dosages of one medication to another when doing opioid “rotations”; and try to avoid prescribing benzodiazepines with opioids (because both classes of drugs can depress breathing).132
In addition, guidelines often suggest that doctors start prescribing opioids slowly and advancing slowly, especially with methadone; assess patients for sleep apnea if they are on higher doses of opioids; tell patients to reduce opioid intake during upper respiratory infections or asthma episodes; and avoid prescribing long-acting opioids for short-term problems such as postsurgical pain.
Assessing a patient’s risk for potential abuse is not as difficult as one might think. In a study of chronic pain patients by researchers from Boston’s Brigham and Women’s Hospital in 2004, Edward Michna and Robert Jamison showed that it’s possible to predict opioid abuse by asking a few straightforward questions.133 Patients who acknowledged a personal or family history of drug or alcohol abuse or a history of legal problems were more prone to the abuse of opioids, including a higher likelihood of lost or stolen prescriptions and the presence of illicit drugs in urine tests.
In 2009, the American Pain Society, the American Academy of Pain Medicine, and the Oregon Evidence-based Practice Center at Oregon Health and Science University published 25 specific recommendations for prescribing opioids, based on an intensive two-year collaboration among 21 experts who reviewed more than 8,000 published abstracts and studies.134 The strongest predictor of possible drug misuse,135 this evidence showed, is a personal or family history of alcohol and drug abuse. For patients who do have such a history, the guidelines advise telling patients to fill opioid prescriptions at only one pharmacy, to submit to random drug tests, to attend regular doctor’s appointments, and to lock medications at home.
Similar recommendations have been promulgated by the Federation of State Medical Boards of the United States.136 These guidelines have been endorsed by the American Academy of Pain Medicine, the Drug Enforcement Administration, the American Pain Society, and the National Association of State Controlled Substances Authorities. Many states have officially adopted all or part of these model guidelines. Still other guidelines have been proffered by a team of researchers from Harvard Medical School and the University of Illinois;137 and other, similar, guidelines from Physicians for Responsible Opioid Prescribing (PROP).138 Advice is also available from the educational group Opioids911-Safety.139
There are numerous recommendations for patients, too, most of which are common sense. Among the dos and don’ts:
Don’t take a pain medication that is not prescribed for you.
Don’t adjust your own doses.
Don’t mix opioids with alcohol.
Don’t take sleeping pills or antianxiety medications along with opioids without talking with your doctor first.
Do be up front with your doctor about all medications and keep track of the schedule on which you take them.
And, given the huge drug diversion problem in the US, do keep medications locked in a safe place and dispose of unused medications.
The state of Utah Department of Health inaugurated a plan incorporating these principles in 2007 and, by the end of 2010, had reduced overdose deaths dramatically.140, 141
But some people feel more drastic action is needed to control opioid abuse. Among them is San Francisco’s Michael Katz, who in 2010 wrote that he has lost so much faith in opioids, at least for long-term use, that he recommends setting limits—a maximum dose—on them.142 This is quite controversial.143 And getting more so. On July 25, 2012, PROP, which opposes much of the current prescribing of long-term opioids, teamed up with Public Citizen’s Health Research Group, an advocacy organization, to file a Citizen Petition to the FDA asking for labeling changes for most opioid analgesics.144
In the petition, the two groups voiced concern about the increase in opioid prescriptions, the fact that many pain patients continue to experience pain despite chronic opioid therapy, and the threat of addiction. The next day, several members of Congress endorsed the petition.145 In addition to concerns about patient safety, the groups said their goal is also to keep drug companies from claiming that opioids are safe and effective long term for non-cancer patients.146
The groups note that the FDA-approved indication for nearly all instant-release opioid analgesics is “moderate to severe pain.” For extended-release opioids, the indication is for “moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.” The groups want the FDA to strike the term “moderate” from the indication for non-cancer pain. They also want drug labels to specify a maximum daily dose equivalent of 100 milligrams of morphine for non-cancer pain and a maximum duration of 90 days for continuous (daily) use for non-cancer pain.147 The groups contend that these indications as currently written are overly broad and imply that the FDA thinks the drugs are safe and effective for long-term use, which the groups believe they are not.
What worries pain patient advocates is that if the FDA did change the labeling in this way, it would mean that only “severe” pain would be an approved indication. Granted, as I discussed in Chapter 7, there is less evidence than everybody would like on the efficacy of long-term opioids. But absence of evidence does not imply evidence of absence. There’s also less evidence that everybody would like on the risks of long-term opioid use.
In any case, it seems unlikely that changing the labeling, limiting daily doses, and limiting opioid treatment to 90 days would fix much, especially since doctors can legally prescribe drugs “off label” and in higher doses than recommended on labels. (My severe neck pain, for instance, lasted about 240 days, not 90. I did not need opioids daily for this whole time, but what if I had?)
There does not appear to be any data to justify a 90-day limit on opioid prescriptions.148 And limiting the daily dose to 100 milligrams also seems arbitrary. Some guidelines suggest a higher threshold, 120 milligrams a day, but even this limit is not absolute. If a patient is still in pain at this dose, the answer, ideally, is not automatically to stop the medication but to do a more careful assessment of the pain problem, and take it from there.
Bottom line? Yes, opioids have plusses and minuses. That’s abundantly clear. But my take is that the PROP folks have hijacked the media and Congress on this one. Let’s hear it for a more moderate approach.