Pain is commonly undertreated, partly as a result of fears about fostering and maintaining addiction in patients treated with opioids for chronic pain. Confusion often arises about the meaning and significance of the physical dependence syndrome produced by chronic opiate therapy.

The popular press has recently focused increasing attention on abuse of prescription opioids. This attention and the response to it may lead to poorly informed clinical and policy decisions. Unfortunately, there are no solid data about the likelihood of developing addiction when treated for pain, and pain patients present special diagnostic difficulties for physicians attempting to evaluate whether a substance use disorder exists. The DSM-IV criteria for substance dependence can easily be misapplied to patients taking prescription medications. Finally, the management of chronic pain in patients with a history of addiction can be particularly challenging.

In this symposium, Dr. Compton explained how to manage pain in drug-dependent patients. Dr. Zacny discussed the abuse liability-related subjective effects of oxycodone in volunteers who do not abuse drugs, and Dr. Schnoll discussed chronic pain, neuroplasticity and pain treatment.

Symposium Chair: Eric Collins, MD, Columbia University, New York, NY

In 1998, the Federation of the State Medical Boards issued model guidelines that state "the Board recognizes that controlled substances, including opioid analgesics may be essential in the treatment of acute pain due to trauma or surgery and chronic pain whether due to cancer or noncancerous origin." This is a switch in physicians’ thinking. For a long time, people believed that physicians shouldn’t give opiate analgesics to people with chronic, nonmalignant pain for fears of patients developing tolerance as well as addictive disease.

This does raise some concerns. If there is an increase in the prescriptions for opioids for chronic nonmalignant pain, questions arise about whether addicts will be created and whether there will be more opioid-related morbidity or mortality.

There are many definitions of opioid abuse. Many of the data sets that physicians look at as indicators of prescription opioid abuse are really just indicators of nonmedical use or of recreational use.

The National Household Survey is a survey of Americans older than the age of 12. Since the mid-1980s, there has been a significant increase in new users who are nonmedically using psychotherapeutic medications. In the mid-1980s, 400,000 people reported new use of an opioid for a nonmedical reason. Now, that number is 2 million people.

When asked if they had used an opioid analgesic for a nonmedical use during their lifetime, during the past year or during the past month, the survey found a significant increase in the number of people who reported nonmedical use of an opioid analgesic between the years 2000 and 2001.

However, the number of people who report the nonmedical use of prescription opioids is dwarfed by the number of people who use tobacco and alcohol and is less than half of the number of people who report smoking marijuana or using hashish or cannabis. It is, however, higher than the number of people who reported using a hallucinogen, cocaine, prescription stimulants and prescription sedatives, and it is much higher than the use of heroin.

In the 1980s, cocaine was the drug of choice. The 1990s have seen an increase in the use of opioids, both prescription and heroin.

Who is using these prescription opioids? The Monitoring the Future Survey examined use in 12th graders. While there was a drop in the late 1980s and early 1990s, an upswing occurred throughout the 1990s. Males tend to use prescription opioids more frequently than females. Additionally, white 12th graders reported significantly more nonmedical use of opioids as opposed to black and Hispanic 12th graders.

OxyContin is a controlled-release oxycodone compound, and the illicit use sometimes involves circumventing the controlled-release formulation. People melt it down or inject it. The highest rates of use of OxyContin are in 18- to 25-year-olds.

Based on available epidemiologic data, prescription opiate abusers are not chronic pain patients. They are people who are primarily recreationally abusing drugs.

It is difficult to determine the predictors of prescription opioid abuse in pain patients. Not enough chronic pain patients are exposed to opioids to determine the risk of developing addiction. Published rates of abuse and/or addiction in chronic pain populations is approximately 10% or less, which is also the rate of abuse and dependence in the general population. This suggests that the known risk factors for abuse or addiction in the general population are probably good predictors for problematic prescription opioid use in chronic pain patients. In the general population, factors such as history of early substance use, personal family history of substance abuse and co-morbid psychiatric disorders predict or correlate with abuse and dependence. These factors are likely to be risk factors for chronic pain patients as well.

Interestingly, a number of chronic pain patients receive their opioid analgesics in methadone maintenance clinics. Some patients with chronic nonmalignant pain may be unable to find opioid analgesics elsewhere and may end up in methadone clinics, or some of these patients may actually think of themselves as addicts.

There is little evidence to suggest that a patient with chronic nonmalignant pain who is responsive to opioid therapy is at increased risk for patterns of problematic prescription opioid use. Those patterns are such things as drug seeking, abuse and addiction. An individual with chronic pain and untreated addictive disease will not get better with an opioid prescription. Someone suffering from active addictive disease is not going to get more functional regardless of how much opioid they obtain.

Because of the difficulty of diagnosing addiction in the presence of pain, the American Society of Addiction Medicine, the American Academy of Pain Medicine and the American Pain Society recently published diagnostic criteria to use with patients who are on chronic opioid therapy for the treatment of their pain. These guidelines encourage physicians to look for the presence of adverse consequences associated with opioid use, loss of control over their use of opioids and a preoccupation with obtaining opioids, despite the presence of what appears to be adequate analgesia.

If the patient is complaining of pain, increase the opioid dose to try to manage the pain. If there is an improvement in function and an absence of toxicity once the dose is increased, the patient may have a syndrome such as pseudoaddiction or therapeutic dependence. A patient who has pseudoaddiction looks like an addict because he or she hasn’t been getting enough medication. This patient may go to multiple providers and may look drug seeking, but, in essence, he or she is just trying to manage pain appropriately.

Therapeutic dependence is a bit different. These patients look like they may be hoarding or trying to get as much opioid as they can. They realize that they are going to feel terrible if they run out of their medication. For example, a diabetic may hoard insulin, but he or she is not an addict.

If, on the other hand, the opioid dose is increased and there is no increase in functioning, physicians may want to consider the diagnosis of addictive disease. If a patient is getting better on opioids, there should be an improvement in functioning. However, if they are suffering from an active addictive disease, their function will not improve.

Another option is that the patient has a type of pain that is not responsive to opioids. Many neuropathic pain syndromes are not particularly responsive to opioids. There is no reason to keep these patients on opioids.

Patients’ levels of functioning are most important. When evaluating their functional restoration, examine their physical capabilities, psychological intactness, family and social interactions, degree of health care use and their drug use for symptom control. These things should be improving if patients are on chronic opioids for the management of pain.

If a patient has chronic pain and a history of or active addictive disease, physicians should first address the addiction. Once the addiction is under control, then the pain can be managed.

The use of treatment contracts is frequently recommended. It is important to define and manage any physical or emotional components of the pain. Evaluate the opioid efficacy with respect to functional status.

Many of the modalities used to treat chronic pain and addictive disease are very similar. The following interventions work well with both addictive disease and chronic pain: cognitive therapy, behavior modification, involving the family in the plan of care, treating concurrent psychological or psychiatric problems, relaxation therapy and group support. Implementing these types of interventions will effectively address both issues.

Abuse liability is the likelihood that a substance or a drug will be abused in the real world. Drugs differ in their abuse liability. For example, with opioids, pure mu agonists have greater abuse liability than mixed agonists and antagonists. Abuse liability testing in humans is done in the laboratory and uses an established methodology that was developed 40 years ago.

If a physician is testing a prescription opioid with unknown abuse liability, he or she will want to test a range of doses of the opioid as opposed to picking one dose, because the effects may be dose-dependent. Additionally, the physician will want to compare it to an opioid with known abuse liability as a benchmark, and he or she will want to use well-accepted measures that are known to predict the likelihood of abuse, such as drug liking, desire to take the drug again and pleasant subjective effects, including euphoria. If people report these things after taking an opiate without any negative effects, then this drug might have high abuse liability or substantial abuse liability in the population that’s being tested.

When doing abuse liability testing, it is best to start off with drug abusers, because, by definition, they are the ones most likely to abuse drugs. It’s also informative to conduct studies in people who are not drug abusers. Testing these people allows for the estimate of abuse potential of a drug in the general population. The estimate of abuse potential in the general population would be overestimated by using only drug abusers. These studies provide a rough estimate for how patients might be feeling under the effects of the drug.

Oxycodone is a semisynthetic compound derived from thebaine, which is an opium alkaloid. The metabolite is oxymorphone, but this metabolite is not thought to produce the analgesic effects of oxycodone. It has been clinically available since 1915, and it is available in a number of different formulations. It is available as a combination product with acetaminophen or aspirin, and it is available now as a single-entity product. Then, there is the controlled-release product, OxyContin.

Given that oxycodone is abused, did abuse-liability testing studies with drug abusers predict this high abuse liability? No abuse liability studies have been conducted with oral oxycodone in drug abusers. This is somewhat surprising because abuse-liability testing with opioids started in the 1940s and has catalogued almost every drug; however, this testing has often not included oral compounds. Other prescription opioids that have not been tested for their abuse liability include oral morphine, oral hydrocodone, oral hydromorphone, oral meperidine and the fentanyl patch.

With the rise in prescription opioid abuse, it would seem useful to conduct abuse-liability studies with both opiate abusers and polydrug abusers including testing the relative abuse-liability of compounds such as pitting oxycodone versus hydrocodone.

Dr. Zacny conducted a study to characterize the abuse liability-related subjective effects of oxycodone in nondrug-abusing volunteers. Most of the volunteers had experimented with drugs, but it was typically fewer than 50 times in their lifetime. The current drug use of these nondrug-abusing volunteers typically included alcohol, marijuana and cigarettes, although dependent tobacco users were not included in the study. Study participants had to have some current use of a recreational drug, usually alcohol.

The study included an equal number of males and females, and their average age was 24 years, with a range of 21 to 39 years. Twelve of the 18 study participants had taken prescription opioids for medical purposes. Three had used opioids recreationally in their lifetimes, but it was fewer than 10 times. All were healthy as determined by a physical. The setting for the study was clinical. Subjects were in beds at all times except for bathroom breaks. One technician was dedicated to each subject. There were six sessions that were approximately 6 hours long.

At each session, subjects would provide a urine specimen for pregnancy testing and for illicit drugs. There was no illicit drug use during the study. Baseline testing of mood and psychomotor performance was conducted. The capsule ingestion was done under the supervision of an anesthetist. Vital signs including pulse oximetry were continually monitored throughout the session. Testing was conducted at fixed intervals for 5 hours after the study participants swallowed the capsules. Release from the lab was approved by an anesthetist. Study participants were driven home by a transportation service and were told to take it easy for the next 12 hours. Pure oxycodone was used, and testing included 10 mg, 20 mg and 30 mg doses. As a comparator, 40 mg of morphine was used.

Lorazepam was also evaluated — 2 mg of lorazepam was used as a benchmark for clinically relevant impairments.

Measures used in the study included the Addiction Research Center Inventory and the Opiate Adjective Checklist, which measured subjective effects and side effects. Other measures included a visual analog scale and a drug effect/drug liking/take again questionnaire. A variant of this questionnaire was given 24 hours later to assess subjects’ overall ratings of drug liking and wanting after they had a chance to experience all of its effects for 24 hours.

A significant increase on the euphoria scale was seen with 20 and 30 mg of oxycodone. Additionally,

there was a significant increase in the visual analog scale measuring elation at 20 mg and a trend toward significance at 30 mg. Regarding pleasant bodily sensations, there was a dose-related increase as the dose of oxycodone increased. There were significant increases in drug liking and wanting to take the drug again.

However, there was also a significant increase in drug dislike with the 20 mg and 30 mg doses of oxycodone. A lot of individual subject variability was seen. Some subjects reported liking the effects of oxycodone throughout the session, and some subjects reported disliking the effects throughout the session. But, most of the subjects liked the effects early on in the session and then certain effects started kicking in later. This was especially apparent at the higher doses of oxycodone. People reported having difficulty concentrating, having unpleasant thoughts, having a heavy or sluggish feeling and feeling nauseous. In fact, a number of people vomited during or after the session.

When asked about their global rating of liking 24 hours later, the oxycodone ratings were no different from that of placebo. During the 24 hours after the drug was administered, people also reported that they felt bad, had headaches, had itchy skin and felt nauseous with the 30 mg dose of oxycodone.

It is important to remember that these effects occurred with acute administration, and this is not the way that the drug is usually given. It is usually given in prescription form four times a day for several days.

Hydrocodone is a semisynthetic derivative of codeine that is indicated for analgesic and cough suppressant effects. While not available as a single-entity product, there are more than 200 hydrocodone combinations currently available. It is one of the most widely abused prescription opioids in the United States. Hycodan is indicated specifically for cough suppression, and it contains hydrocodone and homatropine, which is an anticholinergic that does not easily cross the blood-brain barrier.

Dr. Zacny studied 18 light recreational drug users. The study included equal numbers of men and women, with a mean age of 26 years. Volunteers were exposed to 5 mg of hydrocodone combined with 1.5 mg of homatropine, 10 mg of hydrocodone combined with 3 mg of homatropine or 20 mg of hydrocodone combined with 6 mg of homatropine. Also included in the study were 40 mg of morphine and 2 mg of lorazepam and placebo.

While there was not a significant increase for euphoria with Hycodan, there was a significant increase in feeling "carefree" with the highest dose of Hycodan tested, which is either four times the recommended dose of Hycodan or two times the recommended dose of Vicodin. Increased pleasant bodily sensations were not seen at therapeutically prescribed doses, but they were seen at the 20 mg dose. Drug liking was found at the super therapeutic dose and also with morphine. Additionally, drug disliking was observed with the highest dose of Hycodan. Some subjects liked and disliked the drug effects. Of those subjects, liking always preceded drug dislike.

Pain is not hardwired. There are multiple channels in the body through which pain is transmitted, and there is a lot of plasticity in this system. This system changes with a painful stimulus.

First, there is activation — painful stimulus is translated into chemical and electrical impulses. With this transduction, there is transmission of that signal to the spinal cord and eventually to the brain. When the stimulus is given frequently, there is an augmentation of the effect. This is the windup period, which is similar to the term kindling. As you get these continued effects, changes occur.

Modulation is due to changes in receptors and ion channels that result in peripheral and central sensitization. This means that there is an increased response to a painful stimulus. The pain is not as simple anymore. Changes occur in the central nervous system and the peripheral nervous system that make the skin or the viscera more sensitive to a painful stimulus. There is altered gene regulations and altered connectivity. New dendrites are formed, making new connections both in the spinal cord and in the brain. Due to the release of glutamate, some cell death occurs, forming new systems. When this occurs, there is persistent, pathological pain in the system.

Eudynia is a term for typical pain sensation. There are some specialized receptors for heat or capsaicin, and there is mechanical pain. Changes occur in the system. The cyclooxygenase system starts working. When these signals occur in the spinal cord, activity occurs at NMDA and non-NMDA receptors in the spinal cord. Changes will occur at different levels in the spinal cord. Impulses will go up and down the spinal cord, creating different effects. If there is prolonged stimulation or an increase in intensity of the painful effect of the nociceptor, there will be a release of substance P, neurokinin A and calcitonin gene-related protein, which have profound effects on the nervous system.

Recruitment of the NMDA system results in the windup effect, which results in increased sensitivity to nociception. In transient sensitization, effects are seen at the peripheral receptors. There is release of compounds during the injury, which has many effects on the nerves in the area. This also is translated into central effects, with central receptors being affected. The result of all this is a reduction in the depolarization threshold, meaning that a less intense stimulus is now causing pain. Now, there is cellular activity that outlasts the nociceptive effect, which means that the pain is persistent and that there is a spread to neighboring cells, resulting in an increased area that is now susceptible to the pain.

If the person continues to have pain, he or she will get persistent sensitization, which is termed the maledynia. The patient will experience inflammation and nerve injuries. Some changes occur in the fibers that are transmitting the pain. C fibers and alpha-beta fibers are very important in the sensation of pain. C fibers are fast transmitters. Over time, if there is persistent pain, the alpha-beta fibers take on characteristics of the C fibers. In addition, there is recruitment of silent nociceptors. These are nerve endings that are pain receptors; however, they are not active until they receive a stimulus. The new dendritic formations that occur in both the brain and the spinal cord result in new connections and the spread of the effect. Retrograde transmission is occurring, with various chemicals migrating down the nerves, changing some of the effects that occur. And there is neuronal death from the glutamate release. Neuronal hyperexcitability occurs and is related to a stimulus that previously was not painful.

Sometimes, people will have pain from something that was previously not painful. This does not occur in everybody, and it is not known why it occurs in some people and not in others. However, these are measurable changes that have been documented.

Hyperalgesia is increased pain with mild noxious stimulus. The area that sustained the most severe injury might now have allodynia, which is pain that occurs with a stimulus that is not normally noxious.

The old approach to controlling pain was to palliate, or just give enough to make the person feel better when the pain was there. Now, the aim is preventing the pain or preventing these changes from occurring by giving preemptive analgesia. In the past, low doses of opioids were used. Now, physicians dose to individual needs. There is no maximum dose — the maximum dose is whatever it takes to control the patient’s pain.

Physicians often use combinations of drugs. In addition to opioids, nonsteroidals can be used and are very effective in transduction. Antiseizure medications and benzodiazepines are also used.

With an intravenous patient-controlled analgesia, the patient can take small doses frequently, staying within the appropriate analgesic range. This is the concept behind long-acting oral medications or patches. It is important to keep the patient within that range without having him or her go on a roller coaster ride.

When working with patients who are in pain, contracts or agreements can be very important so that the patient understands what will happen.

Ask patients the following question: "On a scale of 0 to 10, at what point on that scale do you feel the pain is tolerable?" This will give physicians an endpoint to which to titrate the medication. It also helps differentiate the patient who is taking his or her medication appropriately from the abuser. The pain patient will be very satisfied when the tolerable level is reached and will often back off on the amount of medication being taken. The abuser will start to negotiate a new tolerable level. It is important to titrate to the tolerable lever quickly otherwise it is difficult to differentiate the patient who is legitimately requesting more medication to get control of pain from the patient who is requesting more medication to abuse it. 

Once a patient gets to the point where he or she is comfortable, give the patient enough medication to get to the next appointment plus some rescue doses. He or she will need rescue doses in case the pain is exacerbated.

It is important to monitor for lost or stolen prescriptions. Physicians may consider random urine screens to look for illicit and other drugs and also to make sure the patient is taking the prescribed drug. However, hydrocodone and oxycodone don’t show up in standard urine screens. You will need to ask for this specifically.

Use adjunctive medications, and see the patient as frequently as needed. Work with significant others and family members in getting the patients to use the medication appropriately. To withdraw patients, gradually decrease the total daily dose. Don’t increase the intervals between doses because this will place the patient in repeated episodes of withdrawal. Know the pharmacology of the drugs, and document everything carefully. Bring patients in for unscheduled visits if there is a problem. Most importantly, adequately treat the patient to avoid the problems of both pseudoaddiction and the development of chronic pain.