When I began my clinical training in neuro-oncology at Memorial Sloan-Kettering Cancer Center in 1970s, little was understood about how the brain processes and feels pain. For example, fewer than 10 neurotransmitters of any kind were known to exist in the entire brain, and only a small portion of their receptors had been identiﬁed. No one knew how opioid medications like morphine worked. The brain’s own painkillers and the receptor systems on which they acted were just starting to be discovered.
Attitudes toward patients in pain—even those who were dying—were just as primitive. Patients and physicians alike thought that pain should be viewed as a sign that could help the doctor ﬁnd out what was wrong, not as a symptom or a disease entity that should be targeted in itself for relief. Addiction to pain medication, believed to be almost inevitable if such medication was provided, was considered far worse than some “discomfort.”
As a young clinician, I was asked to help start the ﬁrst pain service in an American cancer center, which formally opened at Memorial Sloan-Kettering in 1981. Our clinical work and the work of our laboratory colleagues has produced much new knowledge since then, but, unfortunately, myths about pain and its treatment still thrive and are being reinforced by recent news reports about prescription drug misuse and prosecutions of doctors for “over prescribing.” We need far more research in this area to produce better medications, but the almost 50 million Americans suffering chronic pain need better care now.
We need far more research in this area to produce better medications, but the almost 50 million Americans suffering chronic pain need better care now.
Here, I will share some of what I have seen and learned about treating pain and highlight where more research—and greater understanding by the public and regulators—is urgently needed.
IN THE BEGINNING
I did not make the connection with my life’s work until much later, but my ﬁrst experience of cancer pain was with my mother, who died when I was in my early teens. She never had good pain management, and I certainly observed that, but I completely disconnected it from what eventually became my ﬁeld of research.
In my early medical training, I had picked up the negative attitudes of other doctors toward treating pain, but at Memorial Sloan-Kettering I was seeing the burden of pain in cancer patients and the great potential that lay in understanding its cause and alleviating it. The compelling aspects of cancer pain drew me to the search for better therapies. Our clinical studies focused on doing placebo-controlled, randomized studies of old and new opioid drugs and drug combinations to establish safe and efﬁcacious doses and deﬁne guidelines for their use. One of our researchers,
Gavril Pasternak, M.D., Ph.D., now head of molecular neuropharmacology at Memorial Sloan-Kettering, had been involved in the critical early work of identifying and elucidating the action of opioid receptors in the brain while an advanced doctoral student at Johns Hopkins.
I began to see what actually happened when we treated cancer patients in pain with opioids. I saw how the medications dramatically improved their lives.
I had learned all the myths about opioid medications, but without recognizing them at the time as myths. I thought that they were pharmacologic facts. I thought that the drugs inevitably caused addiction if they were used long-term, that high doses increased the risk, that tolerance would continue to escalate, and that over time the drugs would not even be effective for the pain. Then, I began to see what actually happened when we treated cancer patients in pain with opioids. I saw how the medications dramatically improved their lives. Almost none of the patients developed addiction or what is referred to as psychological dependence. Higher doses were needed for more severe pain, higher sensitivity, or larger people. Tolerance, when it did develop in some cases, came about as a result of the patient’s progressive disease with escalating pain. Increasing the dose was effective in relieving the pain. In short, we could not demonstrate a clear tolerance to analgesia in this patient population. Importantly, however, tolerance— that is, diminishing effect—usually developed rapidly to the sedation and mild confusion, as well as to the potentially deadly respiratory depression, that opioid medications can cause.
ADDICTION: BATTLING THE MYTHS
Our extensive experience treating cancer-pain patients with chronic opioids pointed toward what we later learned about the multitude of endogenous (natural) opioid receptors: Different processes were involved in the development of tolerance to different effects. Researchers have also found that the development of physiological need for the drug (dependence) and consequent withdrawal symptoms involved different processes than the development of psychological drug craving and compulsion to take the drug despite negative consequences (addiction). These differences seem increasingly likely to involve receptor or neurochemical differences in the brain. Almost all of our patients developed physical dependence if they took the drug for weeks or longer, but, when the cause of the pain was effectively treated, they did not want to continue taking the drugs.
I have seen thousands of patients managed well with long-term use of opioids. The only patients who developed drug-use problems were those who had a prior history of drug addiction. Because many of these patients were seriously ill with cancer, we worked out special programs to address both the pain and the addiction behaviors of this group.
I remember one patient, a woman in her forties, who had severe pain from a large lung tumor invading her upper chest and the nerves to her right arm. She was taking high doses of opioids without effective relief. She had a surgical procedure known as a cordotomy, which, by means of a small lesion made in the high cervical spinal cord, interrupts the pain pathways in the spinal cord that go to the brain. Following the procedure, she had no pain and refused to take her pain medications, because she said that she did not need them. Because she refused to taper off the drugs, she suffered withdrawal; but the ﬂu-like symptoms such as abdominal cramping and diarrhea did not trouble her signiﬁcantly. She simply had no psychological dependence on the medication.
One of the hardest groups to persuade to allow treatment with opioids were the parents of children with cancer pain. Some parents feared the medical meaning of these drugs— thinking that if their child took morphine, it meant that the child was dying—and could not accept that possibility. Others were so frightened of addiction that they refused permission to give the medications, even when their children were obviously in pain. As our clinical experience and the experimental evidence for the safety of these drugs in cancer treatment grew, we recognized that we needed to educate both doctors and patients about it.
One of the hardest groups to persuade to allow treatment with opioids were the parents of children with cancer pain. Some parents feared the medical meaning of these drugs—thinking that if their child took morphine, it meant that the child was dying.
One 14 year-old girl and her family let us make a video of her story. She had been treated for a bone cancer in her leg and the surgery required to realign her bones had left her with severe pain. Her surgeon had told her family that she should tough it out, because the operation should not have caused such a high level of pain. When we saw her, she was in agony, crying constantly, curled up in a fetal position and completely unable to function. If she was ever going to be able to walk again, she would have to exercise. We needed to get her pain under control for her to begin rehabilitation.
We gave her methadone and witnessed a transformation that was remarkable. She became a smiling, appropriate 14 year-old girl again. Her parents were amazed. During about ﬁve months of rehabilitation, she remained on tapering doses of methadone and was able to do her exercises and go back to school. Following the completion of her rehabilitation, she was walking again and the drug was stopped. She did not have any problems with either taking it or stopping it.
During the past three decades, we have had thousands of such experiences. We even studied heroin in patients, because heroin was and still is used in the United Kingdom for pain treatment and some groups in the United States were advocating it as better than morphine. We found that, for most people, a wide range of opioids worked equally well and so decided that the political battle to legalize heroin for pain treatment in the United States was not the issue for us. Rather, we needed to address the barriers to adequately treating pain with the available opioids.
We also advocated for patient-controlled use of pain relievers. When we ﬁrst started this, the technology did not exist that is now used to allow patients to push a button to infuse the drugs. We decided to let patients keep pills at their bedside and take them as needed, avoiding the timing problems associated with the vagaries of nursing staff availability. Some people thought that this was a sure recipe for addiction or overdose, believing that patients would simply take as many drugs as possible, as quickly as possible. In fact, however, cancer patients tended to take smaller doses, and often fewer doses, when they knew that they could control their own pain. Since then, psychological research has shown that a greater sense of control over pain actually diminishes the sensations of pain, and patients are effective in timing the administration of their medications, balancing pain relief and side effects.
Psychological research has shown that a greater sense of control over pain actually diminishes the sensations of pain, and patients are effective in timing the administra- tion of their medications, balancing pain relief and side effects.
Unfortunately, news about our innovative practices prompted a visit from a New York State narcotics agent, who advised us that allowing patients to administer their own doses in this way was illegal. We stopped, of course, but this illustrated how law enforcement and regulation can short-circuit promising new approaches in drug administration. Today, patient-controlled delivery of opioid drugs using infusion devices has become standard practice, and better control of pain consistently has been linked to faster healing and better recovery.
THE EXPERIENCE OF CANCER PATIENTS
Back then, almost every notion promulgated about opioid drugs was wrong, and indeed almost completely backwards: the notion of a high likelihood of addiction, the idea that pain was important to healing and that blocking it might make matters worse, the idea that the opioids invariably lose effectiveness. Over the years, clinical experience and data have shown that in the cancer population there is a very minimal risk of addiction, even with large exposure to opioids, and the beneﬁts to patients are undeniable.
The cancer-patient experience in the United States, together with the inﬂuence of a worldwide hospice movement, provided the clinical framework for providing pain relief as an essential aspect of humanizing end-of-life care and helping patients die with dignity. Better pain relief reduced patient requests for assisted suicide and eliminated needless suffering.
National and international surveys report that more than four-ﬁfths of cancer patients have signiﬁcant pain in the last months of life, pain that requires treatment with strong opioids. The World Health Organization (WHO) Cancer Unit took up this issue in its campaign for “Freedom from Cancer Pain,” calling attention to the need for opioids to be available as essential drugs. Embedding the need for pain relief into its international cancer-control strategies, WHO emphasized the need to use the knowledge that we have today to improve the quality of life for dying patients in pain.
Despite WHO’s publication of four monographs describing the need for pain and symptom management and their integration into healthcare programs for cancer, despite the development of a list of essential drugs for pain and palliative care and a host of directives to governments, the majority of people in medium- and low-resource countries around the world have no access to opioid drugs for essential pain relief. According to WHO, developing countries account for four-ﬁfths of the world’s population, but access ﬁve percent of the world’s opioids. In about half of all countries, opioid medications are rarely used, even for the dying. This has stirred new interest in the need to provide pain and symptom management to patients dying with HIV/AIDS, more than half of whom in the last months of life have signiﬁcant pain requiring opioid pain relievers.
Concerns such as addiction, coupled with lack of professional education and a low priority for the care of seriously ill dying patients in pain, continue to limit the availability of opioids around the world.
Unfortunately, concerns such as addiction, coupled with lack of professional education and a low priority for the care of seriously ill or dying patients in pain, continue to limit the availability of opioids around the world. Although there are model programs in India providing morphine to cancer patients and in Uganda to both cancer patients and HIV/AIDS patients, there is still a great need to advance and encourage balanced drug policies that reduce the regulatory barriers and restrictions that limit suffering patients’ access to cheap, cost-effective pharmacologic pain treatment.
As the role of opioids in treating cancer pain evolved, attention turned to the potential of long-term or chronic opioid therapy for patients with chronic non-malignant pain. Clinical studies pointed to the efﬁcacy of opioids in a spectrum of pain states from arthritis to pain that persists after a case of shingles, what is known as post-herpetic neuralgia. Nerve injury pain (neuropathic pain) had traditionally been viewed as resistant to opioid analgesia, but, again, carefully controlled studies demonstrated responsiveness to opioids, albeit often at higher doses than required for somatic (body) pain states.
At the same time, activists and physicians in the United States were pressing for better recognition of the need for pain control. The Joint Commission on Accreditation of Hospitals, designating pain a “ﬁfth vital sign,” now requires healthcare institutions to assess pain levels of patients, manage pain, and provide patients with information about available pain therapies. Physicians, patient advocates, and pharmaceutical ﬁrms began to argue for the need to treat chronic pain and question why opioid drugs would be denied those whose suffering could last decades. Moreover, research has shown that widening the use of prescription drugs such as morphine and fentanyl, mostly for cancer pain, was not associated with an increase in misuse.
courtesy American Pain Society
MISUSE AND MISPERCEPTION
Early in this decade, however, Oxycontin (a time-release formulation of oxycodone) began to be marketed for patients with moderate-to-severe chronic pain, and, between 2000 and 2002, there was a more than fourfold increase in abuse cases reported to hospital emergency rooms. As media reports described how abusers use the drug to get high, addicts readily learned how to defeat the time-release mechanism by snorting, injecting, or swallowing the drug. The high-dose formulation made these methods of taking the drug extremely intoxicating and potentially deadly to naïve users such as experimenting teenagers. What actually gave rise to the epidemic of abuse is still being studied, but the causes likely include diversion of the drug from appropriate channels by means of drugstore robberies, illegal prescribing by some physicians, and diversion by patients. The problems seemed to occur most commonly in rural areas such as Kentucky, West Virginia, and Maine.
It is still unclear to what extent illegal prescription abuse has anything to do with appropriate prescribing for patients with pain, but concern about the growing incidence of prescription drug abuse has led to a greater focus on physician prescribing. A series of high-proﬁle cases of physicians accused of inappropriately prescribing opioids, and, in some cases, causing patient deaths, has added to the concern about prescription fraud and misuse. Law enforcement bodies such as the Drug Enforcement Agency (DEA) are holding doctors criminally responsible if their patients fake complaints, misuse drugs, sell the drugs, or overdose on them. These prosecutions are having a chilling effect on clinical practice, as patients who need large doses bring government attention even when they have a documented pain condition such as multiple sclerosis, failed back surgery, or spinal cord tumors. Testimony in these cases has demonstrated a wide range of opinions on standard doses, the role of opioids, and standards of treatment. What is of great concern is that courts are trying to deﬁne what should be standard medical practice—not only as a matter of legal judgment but as a matter of medical oversight.
What is of great concern is that courts are trying to deﬁne what should be standard medical practice—not only as a matter of legal judgment but as a matter of medical oversight.
Along with my colleagues, I participated in a DEA project to develop a “FAQ” (Frequently Asked Questions) to educate doctors about appropriate prescribing of opioids. The FAQ was published on the DEA Web site in August 2004, but was then withdrawn by the DEA, which claimed it contained inaccuracies—despite extensive collaboration and vetting of the document with leading medical experts on pain. Withdrawal of the FAQ also coincided with its use in the defense of physicians being prosecuted for their opioid-prescribing practices. A group of six past presidents of the American Pain Society, including me, sent a letter to the judge in one such case, disagreeing with expert testimony obtained by the prosecutor about the use of opioids for chronic pain. This expert testimony apparently was considered crucial in deciding some aspects of the case, but it was based on neither evidence nor standard practice.
When a physician is arrested or loses his license to prescribe, his patients are abandoned, their records conﬁscated, and no provision made for the ongoing care of those patients taking opioids. This lack of concern for the patients is at best unprofessional and clearly unethical, yet it has recently affected hundreds of patients in Pennsylvania, Virginia, and Montana.
IN THE BRAIN: VERY REAL, BUT VERY DIFFERENT RESPONSES
Ironically, this backlash against treatment with opioids comes at a time when we are understanding both pain and addiction better than ever before. Neuroscientists have now identiﬁed more opioid neurotransmitters in the brain than the total of all transmitters of all types known before 1970. For example, research has identiﬁed three different families of opioid receptors with multiple subtypes; the ﬁrst such transmitter was isolated only in 1973. In just one class, the mu-receptors, more than two dozen different subtypes have been cloned in the mouse, 10 in humans, and, according to Dr. Gavril Pasternak, “there are almost certainly more.”
Pain is processed in a network of brain systems called the “pain matrix.” This matrix comprises cortical areas near the surface of the brain, emotional regions toward the center of the brain, and sensory areas in several locations. But physical pain and emotional pain are not at all distinct from each other in the brain. Psychological factors like how helpless a patient feels are associated with greater pain processing in sensory regions, not just areas linked typically with emotion. On functional magnetic resonance imaging (fMRI) scans, both the emotional pain of losing a relationship and sensations of physical pain light up an area called the anterior cingulate cortex.
Physical pain and emotional pain are not at all distinct from each other in the brain. Psychological factors like how helpless a patient feels are associated with greater pain processing in sensory regions, not just areas linked typically with emotion.
Meanwhile, addiction researchers are discovering that people who develop drug-abuse behaviors tend not to be pleasure seekers but people who have suffered trauma, such as child abuse, or have had a mental illness, such as depression. Scientists are also ﬁnding genetic factors that appear to predispose people to drug problems.
Dr. Pasternak calls attention to the remarkable diversity of human responses to opioid medications. These responses are so variable that about half of all clinical trials do not ﬁnd morphine to be an analgesic. He explains: “This is not because morphine is not an analgesic—it is— but because there is so much ‘noise’ due to genetic variation that you have a hard time showing it.” He adds that, in rodents, when the researcher uses just one physiologically consistent strain, the data are much cleaner and more obvious.
Dr. Gavril Pasternak's research at Memorial Sloan-Kettering Cancer Center is helping explain the brain's complex responses to opioid medications. (image courtesy Gavril Pasternak)
Opioids are unique in several ways that at least until now have made them indispensable to patients. Unlike acetaminophen, aspirin, or nonsteroidal antiinﬂammatory drugs (NSAIDs) such as ibuprofen, opioids work against pain by means of at least two different mechanisms. In the spinal cord, opioids appear to work directly by preventing some pain messages from reaching the brain at all. In the brain, however, they act even more strongly to combat the distress associated with pain. Patients frequently describe the drugs as distracting them from their pain, saying things like “I still feel the pain, but it doesn’t bother me, now.”
Although the drugs do decrease pain intensity by their spinal cord action, the relief they bring by literally “de-stressing” a patient appears to be greater. No other pain medications have this action and there is no pharmacologic ceiling on the pain relief that they can provide. All of the other commonly used pain killers are limited by their mechanisms of action to treating mild to moderate pain. Even if they did not cause potentially dangerous side effects, such as bleeding in the stomach at higher doses, this limit on their range of effectiveness curtails their usefulness. By contrast, there is no upper limit on opioid dose, providing the patient can tolerate side effects such as drowsiness and the drug’s effect on breathing. If you increase the dose, you increase the pain relief.
“To date, opioids have proven to be the most efﬁcient and effective of all of the different courses of drugs,” says Dr. Pasternak. He notes that there are alternative painkillers that look great in the laboratory, with potency equal to or greater than morphine, but when these drugs reach clinical trials, they all have intolerable psychiatric side effects. As he puts it, “they make you crazy.” Many such drugs, however, act on the brain’s NMDA receptors. Animal research had suggested that by blocking these receptors, tolerance to opioids could be reduced or even eliminated, along with withdrawal symptoms. One weak NMDA-receptor blocker, dextromethorphan (sold as an over-the-counter cough suppressant) seemed promising for use in conjunction with opioids. Unfortunately, it turned out that doses of dextromethorphan high enough to affect tolerance and dependence were also high enough to produce hallucinations and other unmanageable side effects. Thus, this particular approach did not pan out.
CALLING FOR A NATIONAL INSTITUTE ON PAIN
Despite their effectiveness, the opioids remain but part of the pharmacologic approach to managing patients with pain. Researchers are focused on teasing out the molecular aspects of the various kinds of pain mechanisms (somatic, neuropathic, and visceral) and seeking better understanding of the potential of other receptor systems for modulating pain relief. For example, there are exciting studies of the role of sodium, potassium, and calcium channels; the potential role of cannabinoid receptors in analgesia; and the role of targeted toxins.
In recognition of the volume and importance of this research, the ﬁrst decade of the 21st century was designated the Decade of Pain Research. And yet, notwith standing the obvious potential for new discoveries and the urgent need for better therapies, less than one percent of National Institutes of Health (NIH) grants are made for primary pain research. That is despite the fact that about one-in-ﬁve Americans suffers serious chronic pain, and the percentage rises to almost half of Americans in older age groups.
Less than one percent of National Institutes of Health (NIH) grants are made for primary pain research That is despite the fact that about one-in-ﬁve Americans suffers serious chronic pain, and the percentage rises to almost half of Americans in older age groups.
In contrast, about 15 percent of Americans sometime in their lives will have a substance-abuse problem at some level from mild to severe, but ﬁve times more money is spent for research on drug abuse than on pain. In fact, two entire institutes, the National Institute of Drug Abuse (NIDA) and the National Institute on Alcoholism and Alcohol Abuse (NIAA), are devoted exclusively to research on substance abuse and misuse. There have been many efforts to begin to achieve a better balance: repeated NIH workshop recommendations, several Institute of Medicine recommendations, and two State of the Science Meeting recommendations, for example. But we still have no organized government support for either centers of excellence in pain research, which could support clinicians and basic researchers in advancing pain therapies, and no institute to create the necessary leadership to advance pain research and policy in America and to address what has been recognized as a serious public health issue.
What is needed is a National Institute on Pain with a budget at least equivalent to budgets of the institutes on addictions. For, like addiction, pain affects not only the person with the disorder but also his family and his work life. Like addiction, pain robs life of joy and meaning. The outlook for productive research on pain and pain management has never been brighter. A National Institute on Pain could draw the public’s attention to these points, while informing and educating people about opioid medications. It could convey the message, for example, that addiction occurs when a drug makes a person’s life worse, but for pain patients, the very same drug can make life inﬁnitely better. Indeed, an Institute on Pain could bolster support for addiction treatment, as well, by making the research-backed case, along with NIAA and NIDA, that addiction is a treatable disorder, serious but not worse than a death sentence—and not worse than chronic agony. This research could build on long clinical experience with cancer patients to demonstrate conclusively, by means of long-term studies of people with both cancer and chronic non-malignant pain, that addiction is rare in this population.
Like addiction, pain affects not only the person with the disorder but also his family and his work life. Like addiction, pain robs life of joy and meaning. The outlook for productive research on pain and pain management has never been brighter.
We also need better medications, because some pain opioids can relieve only partially and some patients cannot tolerate the doses that they need to get relief. We need medications and other therapies that can help those for whom opioids fail entirely. And we need to ﬁne tune the opioids so that we can match particular drugs with patients for whom they are best suited and avoid giving them to patients for whom they would be ineffective—or likely to have serious side effects because of a patient’s genetic predisposition. For example, about one out of ten Caucasians cannot metabolize codeine, making it for them an ineffective analgesic. Also, because tolerance to various effects such as physical dependence and addiction are separate processes, it may someday be possible to create medications that avoid or reduce problematic processes while maximizing those involved in pain relief. More research on dissociating these effects is needed.
In the past 30 years, we have seen at least some barriers to pain relief—for example, for dying patients—fall dramatically. We are far more aware of the impact of pain on patients and families and of the enormous need for providing approaches that focus on the physical, psychological, social, and spiritual needs of patients and families. Clearly, research on opioid analgesics is not going to be the only solution for all patients with pain. Yet, the role of the opioids today is so central that we need more research to better understand who can beneﬁt from these agents, what risks they impose, and what other drug combinations are effective. Until we have achieved that, though, does it seem reasonable that patients are forced to endure needless suffering because legal or regulatory barriers make existing medications unavailable to them?