While genetic risk, low or high, is a constant in any given patient. Environmental stress can vary. In this context, untreated or poorly treated pain can increase that person's stress level, and push them closer to their addiction threshold. In these cases, when addiction occurs, it is not because of the pain medication per se, but rather the inappropriate drug, dose, or frequency of the medication that may lead to addiction.

Therefore, while healthcare professionals need to be aware of the risks of addiction, the actual risk of addiction is quite low when treating a legitimate pain patient with an appropriate dose of a narcotic.
Pain.com: I have a patient with chronic back pain who requires dose escalations about every 6 months, does this mean that she has become addicted to the medication?

Dr. Marley: What you have described is a patient who has developed tolerance to her pain medication. Tolerance is nothing more than the body's physiologic adaptation to the administration of an exogenous opioid. Many healthcare professionals incorrectly assume that the development of tolerance is an indicator of addiction. In fact, patients develop tolerance to many of the effects created by opioids. Over time, the patient will develop tolerance to the respiratory depression, and cognitive changes which include euphoria, normally associated with opioids. Eventually, tolerance also develops to the analgesic effects of the opioid. Depending on the opioid being used, the easiest way to achieve continued pain relief is to titrate the dose until an acceptable level of analgesia is again achieved.

Analgesic tolerance occurs primarily through the body's increasing production of enzymes involved in the clearance of the opiate. It is also believed that a process known as hyperalgesia, or rebound pain also assists in the development of tolerance. Hyperalgesia occurs more commonly with the use of short acting "prn" regimens, which allow the patient to continually cycle in and out of pain. Hyperalgesic tolerance has also been associated with the long-term use of morphine, and the development of morphine's active metabolite, morphine-6-glucuronide (M6G).

M6G has also been linked to incomplete cross-tolerance associated with long-term morphine use. In fact, when using morphine at high doses due to tolerance, one can often switch to another opioid at 40-60% of what would be considered an equivalent dose, due to the effects of the M6G metabolite.
Pain.com: I have a patient who has been on around the clock opioid therapy for the past 2 months. After her last surgery, she no longer needed the medication, and experienced opioid withdrawal symptoms. Could she have become addicted in just 2 months?

Dr. Marley: Another common misconception about addiction regarding the use of opioids in treating pain, is that of the development of physical dependence. Much like the development of tolerance, the development of physical dependence does not mean the patient has become addicted. Physical dependence, manifested by the development of withdrawal symptoms upon abrupt cessation of use, will occur when anyone has been on around-the-clock opioid therapy for as little as 2 weeks. Therefore, the development of physical dependence will often accompany addiction, but does not necessarily indicate addiction.

For example, most healthcare professionals understand that if you have a patient on prednisone for a month, the patient will become "dependent" on the medication, meaning they will go into steroid withdrawal if not appropriately tapered. This is because the body has adjusted to receiving exogenous prednisone by decreasing its cortisol production. In this case you would not say that the patient is a prednisone addict.

Physical dependence occurs due to the opioid's effect on an area of the brain known as the locus cereleus (LC). The LC is an area rich in nor-epinephrine containing neurons, whose effects are blunted over time. When a patient abruptly stops taking the opioid, there is a corresponding surge of nor-epinephrine leading to many of the traditional withdrawal symptoms including diarrhea, mydriasis, piloerection, and rhinorrhea. Many of these effects can be successfully managed by tapering the drug over 1-2 weeks, and the use of clonidine if necessary.
Pain.com: What are some of the benefits of long-acting opioids?

Dr. Marley: Long-acting opioids, if used appropriately, have the potential to revolutionize pain management. While the obvious benefit is less frequent dosing schedules, and improved compliance. The other benefits include better overall pain management, improved functionality, and a decrease in the overall risk of iatrogenic addiction.

From the standpoint of pharmacokinetics, you want to maintain your opiate trough level at a point that provides consistent pain relief, and you want your peak to be lower than the amount needed to induce cognitive changes. It has been well established that it is easier to prevent, rather than relieve pain. When giving a short-acting opioid, you often produce higher peaks causing more cognitive effects such as drowsiness and euphoria. Often these medications are administered on a prn (as needed) schedule, which inherently means the returning of pain as an indication of when to take another dose. It is this constant fluctuation of opioid blood levels with short acting drugs that causes further pain facilitation, erratic development of tolerance, hyperalgesia, and a greater risk of addiction.

Long-acting opioids on the other hand, are administered around-the-clock, which provide consistent blood levels within the therapeutic range. This results in fewer episodes of pain, and the consistent development of tolerance to adverse effects including respiratory depression and drowsiness.
Pain.com: What is the difference between addiction and pseudo-addiction?

Dr. Marley: Addiction is a compulsive behavior that includes the loss of control over the use of the drug. The Diagnostic and Statistical Manual 4th edition (DSM-IV) describes addiction as the development of a maladaptive pattern of medication use that leads to clinically significant impairment or distress in personal or occupational roles. It includes: a great deal of time used to obtain the medication, or recover from its effects; loss of control over medication use; continuation of drug use after medical or psychological adverse events have occurred.

With pseudo-addiction, patients with severe unrelieved pain can become intensely focused on obtaining relief, and can mimic aspects of drug seeking behavior. This behavior should resolve when adequate pain relief is provided, without evidence of loss of control, escalating, binging etc.

In many cases, a clinician can differentiate between addiction and pseudo-addiction by titrating the dose to achieving pain relief, and monitoring the rate at which the patient claims to develop tolerance and is in need of a higher dose. Tolerance to the euphoria inducing effects usually occurs in 1 to 2 weeks, while tolerance to analgesia generally requires a few months. Of course in this case, one also has to consider the possibility of disease progression or increasing pain severity.
Pain.com: What are some aberrant behaviors that may be more indicative of pseudo-addiction?

Dr. Marley: Aggressively complaining of the need for more pain medication may simply indicate that their pain has not yet been controlled, or they have developed tolerance. Drug hoarding during periods of less pain, especially if they have ever had their medication run out in the past, and had to suffer. Requesting specific drugs, while often cited as a red flag of abuse, can just as easily mean they know what works to ease their pain and they want the drug that works. Openly acquiring drugs from other medical sources can be an indicator that they are unhappy with the quality of care they are receiving. For example, a Rheumatologist may get so focused on the rheumatologic and inflammatory nature of a disease that they may not be willing to write for an opiate. The patient may then seek out a pain management specialist to get appropriate pain relief. Unsanctioned dose escalation or other non-compliance on 1 or 2 occasions, may indicate the development of tolerance and the need to re-assess. Unapproved use of drug to treat another symptom, i.e. sleeping, could again indicate the need to re-assess and possibly increase the evening dose of the medication. Finally, resistance to change in therapy with tolerable side effects and anxiety may also be related to the fear of returning severe pain.

Quite often, these behaviors are simply dismissed as addictive drug seeking behaviors, which causes the legitimate pain patient to be that much more demanding in the treatment of their pain. The challenge to the healthcare professional is to take the time to communicate with the patient, and try to determine what is motivating the behavior they are observing, is it compulsive drug use or untreated pain.
Pain.com: What are some aberrant behaviors that may indicate true addiction?

Dr. Marley: Episodes of prescription loss are a significant red flag. I once heard a physician say that in the 25 years he had been practicing medicine, nobody ever lost a prescription for high blood pressure. Prescriptions obtained from other clinicians, especially from the emergency room, without first consulting with their primary provider is cause for concern. Deterioration in function related to drug use, is an indication of abuse, since the desired effect of pain relief is an increase in overall function. Resistance to change therapy despite significant side effects, is a further indicator of compulsive use. Multiple dose escalations and/or noncompliance with other aspects of therapy. Other more obvious as well as illegal activities include; selling prescription drugs, prescription forgery, stealing or "borrowing" drugs from other than who it was prescribed, obtaining prescription drugs from non-medical sources, and the concurrent abuse of alcohol or illicit drug
Pain.com: How can pharmacists assist in the proper treatment of pain, while trying to recognize and prevent drug diversion.

Dr. Marley: Admittedly, it is a challenge for pharmacists to be ever vigilant in trying to prevent drug diversion and abuse, while not being so concerned about diversion to the point that it negatively impacts a legitimate patient's need for pain medication. Pharmacists can play an active role in monitoring a patient's pain medication regimen, and making appropriate recommendations to the prescriber when appropriate.

A pharmacist can be very helpful by being alert and observing if a patient has been using frequent daily doses of a short-acting opioid. If the patient is experiencing moderate to severe pain, a recommendation of around-the-clock use of a long acting opioid may be appropriate. When used as prescribed, long-acting opioids can often provide better pain relief, and less risk of addiction compared to that of short-acting opioids.

In trying to prevent diversion, it is important for pharmacists to take a moment to review the prescription. If there is anything that looks suspicious, the pharmacists should call the prescriber for verification. Unfortunately, many pharmacists simply take the easy way out by telling the patient, "we don't carry that" rather than go through the verification process. This occurs most often when a legitimate patient is calling the pharmacy to see if the drug prescribed is in stock. Many pharmacists will incorrectly assume that the phone call is from an illegitimate patient, and simply turn them away, not realizing that this is a legitimate patient who has been turned away because "we don't carry that', and is simply trying to find a pharmacy who does.
Pain.com: Is it appropriate to prescribe narcotic analgesics to patients with a history of alcohol or other drug abuse?

Dr. Marley: While one has to take into account a number of factors, when treating pain in a patient with an addiction history, the history of addiction does not necessarily preclude the use of narcotics in treating pain. Unfortunately, many healthcare providers tend to under treat pain in this population, which further increases their risk of illegal drug use or relapse.

If the patient has been in remission from active addiction/alcoholism, you should first attempt non-pharmacologic and/or non-narcotics therapies. However, once these methods have failed, the use of narcotics may be appropriate. In this population, the use of long-acting opioids would be the best choice. Short-acting medications produce significantly greater euphoria, increasing the risk of relapse, and should therefore be avoided in these patients.

For a patient who is currently abusing narcotic drugs, i.e heroin, one should be aware that in an acute pain situation, this patient will already have a high degree of narcotic tolerance and will require much higher than normal doses to achieve pain relief.

In either case, active addiction or in remission, the patient should be well informed as to the risks associated with inappropriately using the medication prescribed, and closely monitored for inappropriate drug use. The prescriber should also be aware of the risk of relapse associated with the use of narcotics regardless of whether the patient was an opiate, cocaine, or alcohol abuser.
Pain.com: Regarding the issue of drug diversion, is further state and Federal regulation the answer to the problem?

Dr. Marley: I do not believe that further regulatory involvement is the answer to the current problem of prescription drug abuse. The profession of pharmacy is already over-regulated, and any further regulatory involvement would have little effect on illegal drug use, and may have a significant negative impact on the proper treatment of pain.

An example of how excessive regulation can have a negative impact on effective drug therapy is what happened when then state of New York started requiring triplicate prescriptions for benzodiazepines. While benzodiazepine use decreased, there was a corresponding increase in the use of medications with a poorer safety profile, such as chloral hydrate and meprobamate.

If we truly want to address the issue of drug abuse, we need our healthcare system to take a serious approach to treating addiction in the same way as we treat other chronic diseases. Unfortunately, most healthcare professionals receive very little formal education about pain management, and even less about drug abuse and addiction.
Pain.com: Thank you Dr. David A. Marley

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