ASRA Pain Medicine Update

Aug 6, 2019, 14:27 PM by Kisha Thomas, MD, and Robert W. Hurley, MD, PhD

Authors

Original Authors

John A. Bailey, MD
Assistant professor
Depts of Psychiatry and Anesthesiology
Division of Addiction Medicine and Pain Management
Program Director, Pain Medicine
Springhill Health Center

Robert W. Hurley, MD, PhD
Associate professor
Depts Anesthesiology, Psychiatry, Neurology
Chief of Pain Medicine at UF
Fellowship Director

Mark S. Gold, MD
Department Chairman
Donald R Dizney Eminent Scholar and Distinguished Professor
Psychiatry

University of Florida
Gainesville, Florida

Revised December 9, 2014, by

Kisha Thomas, MD
Pain Medicine Fellow

Robert W. Hurley, MD, PhD
Professor and Vice Chair

Department of Anesthesiology
Medical College of Wisconsin
Milwaukee, WI

Introduction

Despite the high comorbidity of addictive disorders and chronic pain, little attention is devoted to recognizing and managing addictive disorders in most pain medicine fellowship programs.^[1] The degree of the coexistence of these two disorders is striking. For example, 37% of patients in methadone maintenance and 24% of inpatients in drug treatment complain of severe chronic pain.^[2-3] Conversely, non-cancer patients with chronic pain have a broad prevalence of current substance use disorder (SUD) ranging from 3%–48% and a lifetime prevalence of any SUD ranged from 16%–74% depending on the study and the definition of addiction used.^[4]

Recognizing and treating patients with coexisting addiction and chronic pain is challenging. Pain is subjective and can exist without physical findings, we are forced to rely heavily on what our patients tell us. Addiction short circuits and hijacks the brain resulting in deception towards caregivers, as well as unconscious self deception (denial). Research has shown that physicians are not adept at spotting deception.^[5] Adding to the challenge is evidence that many patients with addictive disorders have a “syndrome of pain facilitation” with anxiety, depression, sleep disturbance, and decreased pain tolerance.^[6-7] In addition, patients with a history of substance abuse may feel scrutinized and stigmatized and be leery of opioid tapering as they attempt to access medical care; meanwhile, providers may grapple with being able to safely provide pain management while maintaining patient rapport.^[8] The number of problems to co-manage in this patient population can seem overwhelming. Conversations with patients on high doses of prescribed opioids can be challenging.

Iatrogenic Addiction

It is still debated whether the long-term use of addictive drugs in and of itself can cause addiction. Historically, it was believed this was inevitable. This was largely due to a lack of knowledge concerning the difference between physical dependence and drug dependence (addiction).^[9] In the 1980s, this belief gave way to the idea that addiction was an extremely rare consequence in the chronic pain population.^[10-11] Today, mounting evidence suggests that the truth is somewhere in the middle. Although there is now evidence that opioids and other reinforcing drugs can produce neuroplastic changes in the brain, the relative ease with which this occurs depends on several variables.^[12-13] These include:

• Family history of addictive disorders, especially in first-degree relatives
• History of post-traumatic stress disorder (PTSD) or childhood abuse
• Chronic stress that can be caused by the undertreatment of pain; the stress from pain augments dopamine overflow in the VTA-MFBAcb reward axis.

Preexisting SUD is a risk factor for poor outcomes in chronic opioid therapy, as these patients often need more intensive treatment to address their pain but rarely receive it.^[14] Though addiction is associated with certain psychiatric disorders, it is not thought to be caused by them. Rather, addiction is believed to be a primary neurobiological disorder. Thus, treating the primary psychiatric disorder will not cure addiction though effective treatment may decrease the likelihood of relapse in those who are recovering from addiction. Therefore, a pain patient presenting with coexisting addiction and a psychiatric disorder needs primary addiction treatment, in addition to treatment for the psychiatric disorder.^[15] However, addiction can mimic many psychiatric disorders, including major depressive disorder (addiction induces anhedonia), generalized anxiety and panic disorder (withdrawal), and even schizophrenia (stimulant toxicity).

Drug Control Measures

Prescription abuse and diversion are enormous public policy issues. Between 2001 and 2005, deaths involving prescription pain relievers increased 114%.^[16] As a result, there is increased scrutiny of pain clinics and practitioner prescribing practices. Many practitioners are experiencing “opioiphobia” and are reticent to prescribe opioids out of fear of licensure and legal consequences. The actual risk of licensure or legal issues is extremely low. However, according to one study, the risk of a DEA investigation was an unreassuring 15%.^[17-18] There are many factors that are correlated with increased risks of licensure or legal issues. These include:

• Poor documentation
• Failure to address addiction issues in patients
• Lack of Board certification
• Poor initial screening and follow-up monitoring
• Inappropriate, non-evidence-based prescribing practices
• Lack of an opioid agreement.

With education, following suggested guidelines and attention to detail, opioids can be safely prescribed without undue risk to both the patient as well as the prescribing physician.^[19-20]

Terminology

Plaguing both the specialties of pain and addiction medicine has been a lack of consensus on terminology and sloppy use of such words as “addiction” and “addictive.” In pain medicine, there is still no universal agreement on the definition of pain itself or even the length of time that must lapse before it is considered chronic. Attempts have been made to standardize the terminology. For example, in 2001, experts from the, the American Academy of Pain Medicine (AAPM), American Pain Society (APS), and American Society of Addiction Medicine (ASAM) met and formed a consensus panel to standardize some of the confusing terminology.^[21] A few examples of commonly used and confused terms include the following.

• Tolerance can be defined as a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effect over time.
• Physical dependence is characterized by a drug-class-specific withdrawal syndrome resulting from abrupt cessation, dose reduction, decreasing blood levels, or administration of an antagonist.
• Addiction is a primary neurobiological disorder or brain disease with genetic, psychosocial and environmental underpinnings. The disease of addiction has behavioral manifestations. According the ASAM, this includes impaired control over drug use, compulsive use, continued use despite harm, and craving. Denial is often observed in addictive disorders, prompting the often-heard phrase in Alcoholics Anonymous (AA) rooms: “Addiction is the only disease that tells you that you don’t have it.”
• Pseudoaddiction is a term used to describe behavior that resembles addiction. These behaviors are characteristic of addiction and may include “doctor shopping,” illicit opioid use, and running out of medications prematurely. However, unlike addiction, they are driven by an attempt to obtain adequate pain control. In pseudoaddition, function and mood improve with an increase in opioids. Conversely, in addiction, function and mood deteriorate as the disease of addiction progresses.
• Chemical coping is a term commonly used to describe the self treatment of mood and other psychiatric disorders. For example, opioids are midbrain dopamine boosters and can produce euphoria, temporarily improving mood. They also are somewhat anxiolytic and sedating. Thus they are sometimes used inappropriately to self treat depression, anxiety disorders and PTSD, as well as alleviate boredom.^[23]
• Drug abuse This is not the same thing as addiction. It is not a primary brain disorder. People abuse drugs to get “high” and experience supranormal euphoria and pleasure. Unlike addiction, neural pathways are normal, and, given the right circumstances or consequences, people who abuse drugs can choose to quit without treatment or maintenance of a recovery program.

In 2013, the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) was published, which revised the section addressing substance abuse disorders on a single continuum.^[24] This strategy removes separate categories for “substance abuse” and “substance dependence.”^[22] Instead of separate but similar sounding terms, there is a list of 11 criteria with a scale addressing the substance abuse disorder as mild, moderate, or severe. Overall, the diagnosis of an SUD is based on a pathological pattern of behaviors related to use of the substance. Criteria for each SUD relate to impaired control, social impairment, risky use of the substance, and pharmacologic criteria.

Neurobiology of Addiction

Addiction is believed to have a neurobiologic basis, and it is helpful to have a basic understanding of addiction science to understand addictive behavior. Addiction-related neurobiologic pathways, though largely detrimental today, may have exerted a positive evolutionary pressure in ancient times. It is thought that we evolved such that substances or activities that perpetuate our species such as food, water, sex, and nurturing trigger midbrain dopaminergic circuits. This activation is often linked with pleasure, pairing an evolutionary hedonic drive to species perpetuating activities. Moreover, this activation is also linked with salience or importance that is separate from pleasure.^[25-26] Most patients who are driven by addiction no longer experience pleasure related to the self administration of drugs. Many are at a loss to explain why they engage in self destructive behavior producing disastrous consequences when it is not even enjoyable. Furthermore, it is not to avoid withdrawal since some of the most addictive substances known such as crack cocaine, produce few withdrawal symptoms.

Projections from the dopaminergic circuit’s active limbic and precortical areas trigger desire, planning, and expectation. They also deactivate other circuits that serve to put the brakes on basic drives after they are satisfied. Addictive drugs such as opioids activate these circuits even more than natural reinforcers. This dopaminergic activation serves other functions such as embedding emotional memories thus priming the brain to react emotionally and motivationally in response to triggers (people, places, and things), drug exposure, and even the expectation of drug exposure. As mentioned, this activation is accompanied by deactivation of areas involved in rational thinking and impulse control that would serve to restrain self destructive behaviors.^[27]

Addiction is thought to be largely a result of baseline low midbrain dopamine. This results in an exaggerated dopaminergic response to dopamine-increasing drugs along with decreased inhibitory control. These brain changes are in a large part hereditary though prolonged or traumatic psychological stress (often from chronic pain) or possibly prolonged drug exposure can result in the “all go” and “no no” brain circuit response to drug exposure, triggers, or even the expectation of drug exposure. In a sense the neurocircuitry changes produce a hijacking of the brain whereby those with addiction are “not themselves” in response to drug triggers.^[28] Typically, denial is a large component, and the inability for an addict to appreciate the existence or magnitude of his problem is mystifying to others. The drive to obtain dopaminergic drugs is so powerful that addicts will cross moral and ethical lines that were inconceivable to them prior to manifesting addiction. However, not being true sociopaths, they will experience guilt, remorse and shame over their behavior, which also drives self medication to escape these feelings.^[29]

Moreover, those suffering from addiction will be at a loss to understand or explain why they do what they do. Typically, drugs such as opioids when taken chronically do not produce pleasure or euphoria. Therefore addicts, when under the spell of addiction do not experience pleasure from the drugs. They also do not experience pleasure from typical life experiences. This may be the result of down regulation of dopamine production producing baseline anhedonia.^[30] This is largely indistinguishable from major depressive disorder. However, after opioid detoxifation, and some normalization of midbrain dopamine, depression often lifts and may not ever recur during sustained recovery.^[31] The socioeconomic losses, shattered relationships, and legal consequences add to the devastation, eventually producing the “incomprehensible demoralization” that can drive addicts to finally seek treatment, or, unfortunately, all too often, commit suicide. Addiction is a life-threatening disease, with a very high mortality.

Looking at the neurobiology through an evolutional framework, the drive to increase midbrain dopamine served to perpetuate the human species since it translated to increased drive to obtain food, nurturing, and procreation. Those with “addiction neurocircuitry” were probably overachievers when it came to these species perpetuating activities. However, the development of drugs that increase dopamine on an exaggerated level compared to natural reinforcers threw a wrench into the otherwise species perpetuating machinery.

However, addictive behavior (not necessarily addiction) can also occur in people without “addiction neurocircuitry.” As mentioned, in pseudoaddiction. pain relief is the primary motivation. Furthermore, drug abuse can occur whereby euphoria, relaxation, or relief of boredom is the motive. Chemical coping can also be the driving force behind addictive behavior. This occurs from the self treatment of conditions such as depression, anxiety, PTSD, or sleep disorders. Also, the avoidance or relief of addiction-induced anhedonia as well as the extreme anxiety that occurs as a result of sympathetic nervous system overactivation during drug withdrawal can be a significant driving force. It seems that the magnitude of physical withdrawal symptomatology can differ from person to person. It is important to remember these symptoms are due to physical dependence and not necessarily indicative of addiction. Finally, behaviors that appear to be addiction, pseudoaddiction, or chemical coping such as running out of medications early, escalating doses, and requesting more reinforcing drugs may be secondary to diversion for monetary gain. Many drugs have high economic value and can be sold to supplement or replace income.

Differentiating these sources of addictive behavior represents one of the greatest challenges to those practicing pain medicine since the appropriate response varies. For example, those with addiction or psychiatric disorders need treatment for a disease. Those who are abusing drugs need to be stopped. Those who are selling drugs need to be stopped and turned over to legal authorities.

Addiction treatment and a recovery program can somewhat normalize addiction neurocircuitry and eliminate addictive behavior. However, the vulnerability to return to addictive behavior is lifelong. Thus, one is never really cured from addiction.

It is also important to realize that drug detoxification is not the same as addiction treatment. Detoxification alone does virtually nothing to lessen the likelihood of returning to addictive behavior. Patients who claim that they are “cured” from addiction and can thus return to controlled use are destined for failure.^[32]

Relationship of Pain and Addiction

As mentioned in the introduction, the coexistence of pain and addiction is common and there are several caveats that stem from this relationship. First, the stress from chronic untreated pain may trigger neuroplastic changes that can result in addiction, especially in those who are predisposed. Indeed, there is evidence to suggest that for those who suffer from coexisting pain and addiction and who are in good recovery from addiction, adequate and appropriate pain control, even via opioids, can actually lessen the likelihood of relapse. However, the inappropriate use of pain medications to treat pain can increase the likelihood of relapse.^[33]

Treating pain in those with coexisting addiction requires a thorough knowledge of both pain medicine and addiction. Psychiatric evaluation and management are often necessary for individuals with complaints of pain that are disproportionate to what would be expected for their condition, psychiatric or substance use-related comorbidities, inappropriate demands for medication, or poor response to treatment.^[34] The concern for patients who meet these criteria is that they may have difficulty with psychosocial factors contributing to pain, treatment compliance, and the potential for pain medication misuse and addiction. Specialists from both pain and addiction should be working together, or pain management should be provided by dual specialists, preferably evidenced by Board Certifications in both pain medicine and addiction. To treat and monitor these patients, it is also helpful to have a thorough understanding of recovery programs.^[35]

Medication Considerations

Pain medicine practitioners should have a thorough understanding of the effects of the drug—usually opioids—its delivery system,and the effects of the environment on drug reinforcement. In general strong Mu agonists are more reinforcing than weak agonists, partial agonists, or mixed agonists. Furthermore, opioids and other drugs that are short-acting or release rapidly are more reinforcing than long-acting or sustained-released drugs. This follows from the fact that it is not just the amount of dopamine rise that determines reinforcement but also the rapidity of rise.^[36] Thus, rapid-release hydromorphone and oxycodone are more reinforcing than slow onset medications such as methadone or sustained-release morphine.

Furthermore, attention must be given to the ease of defeating the delivery system. For example, though sustained-release oxycodone and fentanyl patches produce relatively stable blood and brain concentrations, their delivery systems can be defeated. Furthermore, some varieties of sustained-release drugs, such as oxycodone, are designed where one-third of the drug is released up front to provide more rapid relief. Though this can be perceived as a positive, it also makes the medication more reinforcing, increasing its abuse liability. It is also possible that the overuse of short-acting breakthrough opioids produce “mini-withdrawal” several times a day, destabilizing mood, increasing pain, and setting up expectancy for the next dose. In addition, rapidly releasing opioids chronologically tie the effects of the drug more firmly to drug administration. This increases dopamine release that is tied to expectancy. Finally, there is evidence that drugs taken recreationally are more reinforcing than the same drug administered in a controlled, directed clinical setting, especially when taken for pain. In this sense, pain itself could actually be somewhat protective from the “addictive” neuroplasticity changes that opioids could potentially induce.^[37]

Patient Care

A proper initial evaluation of a potential pain patient is often a complicated and arduous task. Optimally, it should include addiction screening, addiction and opioid risk assessment and stratification, as well as a psychological screening. This alone can be time consuming and difficult, especially considering the fact that patients who are in suffering from addiction or abusing or selling drugs are not forthcoming. The use of standardized tests such as the Screener and Opioid Assessment Tool (SOAPP) and Opioid Risk Tool (ORT) can be helpful in identifying patients at risk.^[38-39] The fact that pain is subjective and can present without objective physical findings adds to the difficulty. Patient records are needed along with clear-cut documentation of an actual pain condition if the cause has been diagnosed. If not, diagnosis must precede treatment. Adding to the difficulty is the not uncommon situation where a patient shows up with obvious physical findings such as reflex changes, antalgic gait, and surgical scars, lacking adequate documentation, running out of opioid analgesics, and at risk of withdrawal.^[40]

Also a challenge and even more common, is the patient who arrives on a medical regimen that defies reason in terms of quality and quantity. All of us have seen patients who arrive on their first visit with real pain, adequate documentation on horrendous regimens that include TID benzodiazepines, qid carisoprodol, q 4 h 30 mg prn rapid-release oxycodone, and enough long-acting opioid to overdose a small army. Add this to a health insurance policy that will not cover detoxification or drug rehabilitation services, and you have the makings of a real challenge. Those of us who truly want to help these patients, rather than resort to the easy out of “I only do procedures,” are engaging in what is probably the lowest financial reward divided by risk-challenge-aggravation ratio encountered in all of clinical medicine.

Red Flags

What follows is a list of red flags from the literature and the authors' personal experience that point toward an increased risk of addiction, abuse, and diversion.

• Young age
• Personal history of addiction or drug treatment
• Family history of addiction, especially in first-degree relatives
• Claim of being in recovery but lacking a recovery program
• Tobacco use
• History of physical emotional or sexual abuse
• Personality traits such as thrill seeking and risk taking
• Lack of objective findings
• Perceived overexaggeration of physical symptoms
• Lack of documentation
• Requests for specific, highly abused medications
• “Process” addictions such as food, sex, and gambling
• Lack of honesty in history (arrests, treatments, etc)
• Driving long distances
• Refusing contact information or not signing information releases
• History of ER visits, multiple doctors, multiple pharmacies
• Claim of having a high tolerance
• Claim of allergy to less reinforcing, less abused opioids
• Cannot produce urine
• Knowing too much about controlled medications
• Problems with life relationships or jobs
• History of teenage tobacco or cannabis use
• No medication bottles or documentation
• Drug-related tattoos or seed burns
• Physical findings such as “tracks,” Hepatitis B or C, HIV, liver function tests
• Lack of interest in non-controlled drug medication therapies
• Focus on opioids
• Lack of interest in interventional techniques that may be helpful
• Certain psychiatric illnesses such as PTSD, bipolar disorder, depression
• Withdrawal symptoms and intoxication symptoms
• Use of street terms such as “Roxies,” “Xanny bars,” and “bars”
• Paying cash
• Asking for controlled medications that insurance won’t cover
• Discharge from other pain physician

The Patient with Coexisting Pain and Addiction

Comanaging pain in those in recovery from addiction is possible with the goal of minimizing pain and the likelihood of relapse. This can be very difficult because while re-administration of opioids is a powerful relapse trigger, untreated pain is also a potent relapse trigger. Optimally this should involve either the combination of separate addiction medicine and pain medicine specialists or a practitioner who is trained in both specialties. There are some helpful guidelines though none are absolute; individuality of the patient and the situation must be considered.

Because addiction is a disease, and not a group of separate diseases, those who have a history of alcoholism are at risk of losing control of any scheduled medications. The administration of a nonopioid reinforcing drug such as alcohol or benzodiazepines will also wake up the addictive midbrain circuits and increase cravings for opioids. Therefore all addictive-dopamine increasing drugs are considered unsafe for those in recovery, and their use must involve a careful weighing of risks and benefits.

For patients with both chronic pain and substance abuse, comprehensive management is necessary.^[34] Baseline information includes diagnosing the pain condition, substance-use diagnoses, and psychiatric comorbidities. A full assessment of current psychosocial circumstances stressors, susceptibilities, and strengths should also be included because patients with severe stress may have a risk of untreated chronic pain and patients with active substance abuse will need a specialist rather than an independent primary care physician or pain specialist. Communication is essential as the risk of relapse of addiction or misuse of opioids must be recognized and expected. Given this set of risks to the patient, treatment that maximizes nonopioid pain treatment is advisable.

Management

There are several basic principles in the medical management of these patients. First, opioids should not be considered unless other modalities have been exhausted or are inadequate. Second, if opioids are deemed necessary, avoid the use of short-acting opioids or breakthrough pain medications. Long-acting opioids should be carefully chosen with attention paid to the ease of defeating the delivery system. For example fentanyl patches can be orally ingested or their contents injected (often with disastrous consequences). Oxycontin can be crushed and snorted, as can most controlled-release morphine preparations. Abuse-deterrent formulations for oxycontin have been on the market but, in general, data based on representative retail, mail order, and long-term care pharmacy sales indicate modest declines in oxycontin sales which level off after a year.^[41] Furthermore, evidence suggests that most opioid abusers swallow the intact pills. Street value is a fairly good guide, and our addiction medicine colleagues can be helpful in this respect. Buprenorhine should be considered if an opioid is required, though its use is off label, and many insurance companies will refuse to pay for it, especially without a 304.1 opioid dependence ICD9 code. It is discussed separately below.

Soma, Fiorinal/Fioricet, and tramadol should be avoided. Tramadol, though non-controlled, is an opioid analog and can trigger relapse. Many cases of addiction have been reported with all of these medications. Furthermore, all benzodiazepines should be routinely avoided. If needed, which is exceedingly rare, long-acting benzodiazepines such as clonazepam are preferable. These should only be taken at night in most cases. Most sleep medications are not considered safe and can trigger relapse or even become the drug of choice. Thus zolpidem, eszopiclone, and zaleplon should be avoided in the vast majority of patients with a history of addiction, drug abuse, or even strong risk factors.

If a stimulant is indicated to counteract opioid sedation or control a medical condition such as sleep apnea, or narcolepsy, use of long-acting, controlled-release forms are preferred. Though not technically a stimulant, modafinil may be the safest choice and should be considered over the others.^[42]

Psychiatric comorbidity such as PTSD, depression, and bipolar disorder should be treated, and consideration should be given to utilizing a psychiatrist or psychologist. It is necessary to monitor recovery efforts. Questions regarding AA or Narcotics Anonymous meeting attendance are helpful. It is reasonable to inquire about their location and time. Meeting schedules are readily available over the Internet and can be checked. It may be helpful to ask to talk with the patient’s recovery sponsor. Questions such as “what is the 6th step in AA/NA” are helpful. Generally these steps are recited at the beginning of every meeting and are easily recalled by those who are actually attending meetings.

Medications and monitoring should be tightly controlled. Return visits should be frequent and urine drug testing (consider witnessed) are necessary, including sendoffs that cover a wide range of abusable drugs not measured in conventional office screens. Use ethyl glucuronide (EtG) for alcohol because this test will detect alcohol consumption up to 80 hours after ingestion. A breathalyzer needs to be available. Hair testing is extremely accurate and virtually impossible to defeat. Count pills on return visits, and consider having an invested loved one administer the controlled medication.

During return visits, watch for signs of deterioration such as weight loss, depression, withdrawal symptoms, anxiety, needle marks, less attention to grooming, relationship problems, and work problems. Missing appointments, not being able to produce urine, lost or stolen medication, and running out of medication early are very worrisome. Furthermore, be prepared to have the patient readmitted into treatment if necessary. It is important to have established ties with addiction medication specialists and detoxification and treatment options. In difficult cases, addiction medicine consultation or admission into a 96-hour observation program may be needed.

Buprenorphine

Sublingual buprenorphine is very useful in managing chronic pain patients with coexisting addiction. It has a long track record overseas in treating both pain and addiction. Currently in the United States it is only FDA approved for addiction as an opioid replacement, much like methadone. Though abusable (also like methadone), it is believed that the stable elevated midbrain dopamine levels produced by its chronic administration restore normalcy to midbrain dopamine and decrease cravings. Unlike methadone, it attaches to, stimulates and then blocks the opioid receptors. Thus it serves the dual function of “protecting” the patient from other opioids since other opioids would not be able to attach to the Mu receptor. Buprenorphine is a partial agonist that produces incomplete Mu receptor activation on the order of 50%–60%. It is an effective pain medication and was judged as being as effective as a fentanyl patch in one European study.^[43]

Since buprenorphine incompletely activates the opioid Mu receptor while powerfully attaching to the receptor, patients who are taking full agonist will experience withdrawal. This follows from the fact that buprenorphine has a greater affinity for the receptor than the other opioids and will displace them from the receptor. However, since buprenorphine only partially activates the Mu receptor, the patient will experience acute withdrawal as the receptor activation abruptly drops from full to partial activation. Conversely, if the patient withholds his or her opioids long enough to experience moderate withdrawal, the administration of buprenorphine will acutely take them out of withdrawal.

Patients taking buprenorphine chronically may have buprenorphine attached to their opioid receptors for days after cessation. Thus when patients taking buprenorphine require elective surgery or need extra opioids for other reasons, it may take several days before enough buprenorphine leaves the receptor to allow binding of other opioids. However, if emergency surgery (e.g., trauma) or pain relief is needed, fentanyl, sufentanyl, or possibly dilaudid may have enough receptor affinity to provide opioid analgesia.

When a patient with significant chronic pain issues is admitted into a drug treatment program, a reasonable approach is to start buprenorphine to ameliorate withdrawal during the drug detoxification phase and continued it post treatment for analgesia. Buprenorphine is a schedule 3 medication. To prescribe it for addiction, one has to have completed a training course and register with Substance Abuse and Mental Health Services Administration (SAMHSA) to obtain the “X” Drug Enforcement Agency (DEA) number that is required. However, as is the case with methadone, it can be prescribed for pain without taking the buprenorphine course or obtaining the extra DEA license number.

Buprenorphine is available in two sublingually administered dosages, 2 mg and 8 mg. It comes in two formulations, Suboxone and Subutex , the only difference being the addition of naloxone to Suboxone. Frequently physicians are confused as to the reason for the added naloxone. It is important to realize that the only reason it is added is to decrease the likelihood of IV administration, and thus decrease “street” desirability. Otherwise, the naloxone is inert clinically if taken sublingually as prescribed. Thus, there is no difference between the two clinically. The withdrawal experienced if Suboxone (naloxone containing) is given too early to one who is taking a full agonist has nothing to do with the added naloxone (unless crushed and taken IV, of course) but is only due to the drop in receptor activation secondary to the buprenorphine.

Subutex is the buprenorphine-containing drug of choice for women who are pregnant since it does not contain naloxone, though this has never been shown to be of any harm to the fetus. Both Suboxone and Subutex are relatively expensive, and most third party payers will refuse to cover off-label use for pain management. Recently, Subutex has been produced in a less expensive generic form.

Buprenorphine is touted to cause less “mental clouding” and thus may be useful for those who cannot tolerate conventional opioids. Though controversial, there is also evidence that it may not produce opioid-induced hyperalgesia and may in fact reverse it. It should be considered for those pain patients who are at increased risk for suicide since, as a partial agonist, it does not produce the same degree of respiratory depression as a full agonist. However, when used IV or in combination with benzodiazipines, the risk of respiratory depression is increased, and fatalities have occurred.^[44]

Monitoring Substance Use

Monitoring is recommended to identify current medication utilization and adverse effects, justify ongoing treatment, evaluate compliance, and investigate misuse and abuse. Risk stratification may be useful for determining the frequency of screening.^[45] Effective monitoring involves multiple sources including patient interviews, information from caregivers, prescription-monitoring programs, and urine drug testing. Screening tools such as the SOAPP and ORT are useful while establishing care, along with further monitoring for aberrant behavior with screening tools that evaluate variables such as focus on opioid use, opioid overuse, low functional status, and exaggeration.^[46]

Drug Testing

Routine random drug testing should be done at least twice a year. In those with a history of addiction or aberrancy, consideration should be given to more frequent testing. The commonly used pre-work screening test (SAMHSA 5) is insufficient for pain management screening since it may not pick up many commonly used prescription drugs such as hydrocodone, methadone, hydromorphone, fentanyl, clonazepam, methylphenidate, zolpidem, and carisprodol. Specialized tests that pick up most abused prescription and street drugs are available. Most good testing companies have experts and medical review officers (MROs) available to explain the nuances of their tests.

Urine drug testing has limitations. For example, alcohol is not picked up by urine drug testing. However, a useful urine screen for recent alcohol consumption is EtG levels. EtG testing reliably detects alcohol consumption up to around 80 hours. The usual cutoff for a positive test is around 500 ng/ml though purposeful alcohol consumption usually results in much higher levels.^[45]

Hair testing is extremely accurate, difficult if not impossible to defeat and has become available for most controlled and illicit drugs. Results are not affected by hair dye or bleaching. If head hair is absent, axillary, pubic, or chest hair may be used. Fingernail clippings can also be tested. Limitations of hair testing include recent drug use within the past week. Because THC levels in hair are relatively low, hair testing may not reliably pick up occasional cannabis use.

Urine drug testing is fairly accurate and noninvasive. Measurements of temperature, specific gravity, and urine pH are helpful in identifying aberrancy. Urine temperature should be 90-100° F within 4 minutes of voiding. Temperatures outside of this range suggest substitution or possibly dilution with another liquid such as tap water. A creatinine that is less than 20 mg/dl or specific gravity less than 1.003 suggests dilution, often by the ingestion of copious amounts of liquids. A pH of less than 3 or greater than 11 suggests adulteration. “Clean” urine and devices that keep urine warm and are difficult to visually detect are available over the Internet. Close observation during urine drug screens may be warranted.^[47]

Aberrancy

An opioid/clinic agreement is mandatory and most pain practitioners are familiar with their use. Some forms of aberrancy are indicative of addiction, abuse, or diversion, and others are suggestive and warrant scrutiny.^[48-51] Examples include:

• Buying, selling, and trading prescription drugs
• Illicit drug use
• Urine drug screen (UDS) showing illicit or nonprescribed drugs
• UDS devoid of drugs that are being prescribed
• UDS diluted, substituted, or adulterated
• Inability to produce urine
• Forging or altering prescriptions
• Crushing, snorting, or injecting medications
• Frequent request for dose escalations or “desirable” street drugs
• Falls, accidents, altered mental status, sedation
• Withdrawal signs and symptoms
• Stolen of lost medications
• ER visits, multiple prescribers or pharmacies
• Deterioration or lack of improvement with medication increases
• Frequent calls, requesting early visits or requesting early refills for out of state trips.
• Friday afternoon calls or calling when the primary provider is vacationing.
• Suggestive behavior or clothing
• Claims that only highly reinforcing medications work
• Allergies or reactions to less-reinforcing medications
• Requesting more breakthrough medications
• Physical signs such as unkempt appearance, tachycardia, bradycardia, altered mentation, and needle marks
• Bruises, nose bleeds, weight loss, slurred or rapid speech, dilated or constricted pupils, impaired cognition
• Worsening of psychiatric conditions
• Refusing to sign releases or provide contact information
• Concerned family and friends
• Psychiatric problems such as depression and anxiety
• Isolation
• Deterioration of relationships, job performance problems, and job absences.

The proper response to aberrant behavior takes knowledge, tact, and judgment. It is important to carefully go over the opioid agreement and clinic rules on the first visit. If the patient is thought to be suffering from addiction or relapse or is in recovery, an addiction medicine referral or an evaluation is warranted. If warranted, the patient should be admitted into a drug detoxification facility, followed by a drug treatment program. Often major obstacles encountered are the lack of insurance or insurance clauses that exclude addiction treatment. Patients who are in denial or for other reasons refuse to go to addiction treatment should probably be tapered off all controlled medications. Often, the wish to have their pain controlled is a powerful motivator to get these patients into treatment. Patients do not have to initially believe they have a problem or be motivated for addiction treatment to work. Often acceptance occurs while in treatment. If patients are a risk to themselves, many states have laws whereby patients can be mandated to undergo an inpatient evaluation. It is important to realize that addiction is a life-threatening brain disease. Simply discharging a patient who is suffering from addiction is not only bad medicine but unethical. After completing a treatment program, patients can often return to having their pain managed. This is best done by professionals or groups that utilize both pain medicine physicians and addiction medicine specialist. Some pain providers are also addiction medicine specialists and can provide optimal care.

If it is suspected that patients are abusing their medications, a reasonable response would be discontinuation or a rapid taper of their controlled medications and continued management using only noncontrolled medications. Another strategy would be tightening up follow-up care by increasing the frequency of visits and testing. Occasional hair testing may be helpful. Those who abuse drugs, and are not suffering from the disease of addiction can choose to quit. If another infraction occurs, a no controlled drug regimen or clinic discharge should be considered.

Furthermore, if it is determined that the aberrancy is due to pseudoaddiction and the patient lacks tolerable pain control, dosage adjustment, cross tapering to a different opioid, detoxification followed by opioid resumption, adding other adjunctive medications, or a consult to pain psychology may be very beneficial. It is important that patients understand the limitations of opioid analgesia. Reasonable pain reduction is on the order of 30%-50%.^[52] Patients who are forced to live in pain can learn coping mechanisms that reduce suffering.

Another reason for aberrancy occurs as a result of the patient attempting to self treat a psychiatric disorder such as PTSD, anxiety, or depression. Referral to a psychiatrist or psychologist should be considered. It is important to remember the increased incidence of PTSD as well as depressive, anxiety and sleep disorders in this population. If the psychiatric comorbidity is ignored, interventional and medicinal treatments will likely fail.^[53]

Unfortunately, diversion does occur. Urine drug screens that are negative for the drugs that are being prescribed and requests for drugs that have high street value are very concerning. If proven, reporting the patient to the authorities should be considered. A difficult situation arises when drug diversion is suspected but cannot be proven. One suggestion is to obtain witnessed urine drug screens, consider hair testing to ensure that the patient has been continuously taking the prescribed medication, remove all drugs with high street value, have the patient come in for frequent appointments, perform unannounced pill counts, and obtain collateral information from physicians, family members, and others if appropriate. A simple Internet search for drug-related arrests or a call to all law enforcement may be helpful. If the medications are not present on screening office test, first question the patient about how he or she has been taking the medications. For example, ask "How many pills did you take this morning? How about yesterday? What about the day before?” Then, question the patient about the drugs being absent in the screen. Depending on the situation, consider providing a few pills to hold the patient over until the confirmatory screen is available and arrange a return appointment a few days later to discuss it. Patients who are diverting tend to not return to go over the confirmatory. Consideration should be given to reporting these patients to law enforcement. In addition, carefully look at medications. Patients may lie about having the flu when producing a negative urine drug screen. Close inspection of the capsules may reveal that they have been refilled with grains of rice or pills may be substituted with similar looking over-the-counter medications.

Sometimes irresponsibility and a lack of knowledge are the reasons behind violating the opioid agreement. If this is the case, the agreement must be reviewed with the patient. Receiving opioids for pain mandates a high degree of responsibility. Missing appointments, lost or stolen medications, and attempts to reschedule early may imply a lack of responsibility, which may negate the use of opioid therapy for pain. Consider asking for a police report in the event of stolen medications and not replacing them. Pill counting is an extremely useful tool. Patients need to always bring their pill bottles for counting. Care should be taken to watch for early appointments and to write “do not fill by…(date)” if they need to come in early for scheduling reasons.^[54]

Summary

In summary, like any other medical disorder, patients who are suffering from addiction need diagnosis and treatment. If they have coexisting addiction and chronic pain, both must be addressed or neither condition improves. Addiction is a life-threatening disease. Without treatment the inevitable outcome, as often heard in the rooms of AA or NA, is “jails, institutions, or death.” Pain medicine practitioners are in a good position to recognize and diagnose addiction and help patients get into treatment. Finally, chronic pain patients who are in recovery from addiction need adequate pain control since pain is a potent trigger for relapse. With proper medication choices, monitoring, knowledge of addiction, addiction treatment and recovery, these patients can be successfully managed.

Acknowledgment: Thank you to Dr. Mark S. Gold and Dr. John A. Bailey for their efforts on the first version of this web article.

 

References

1. Polydorou S, Gunderson E, Levin F. Training Physicians to Treat Substance Use Disorders. Current Psychiatry Reports 2008;10:399– 404
2. Modesto-Lowe V, Johnson K, Petry N. Pain Management in Patients with Substance Abuse:Treatment Challenges for Pain and Addiction Specialists. The American Journal on Addictions, 2007;16:424–425
3. Doweiko H. Concepts of Chemical Dependency p41 Publisher: Brooks Cole; 7 edition (February 25, 2008)
4. Morasco B, Gritzner S, Lewis L, Oldham R, Turk D, Dobscha S. Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder. Pain. 2011;152(3)488-97.
5. Jung B, Reidenberg M. Physicians Being Deceived. Pain Medicine 2007; 8:433
6. Compton P, Charuvastra V, Ling W. Pain intolerance in opioid-maintained former opiate addicts. Drug Alcohol Depend 2001;63:139-146
7. Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage 1994;9:462-473
8. Merrill J, Duncan M. Addiction disorders. Med Clin North Am. 2014;95:1097-122.
9. Courtwright D, Dark Paradise: A History of Opiate Addiction in America, t.Publisher: Harvard University Press; Enlarged edition (May 31, 2001)
10. Porter H, Jick H. Addiction rare in patients treated with narcotics (letter), N Engl J Med 1980;302:123
11. Portenoy R, Foley K. Chronic use of opioid analgesia in nonmalignant pain: Report of 38 cases. Pain 1986; 25:171-186
12. Brady K, Sinha R.Co-Occurring Mental and Substance Use Disorders: The Neurobiological Effects of Chronic Stress . Am J Psychiatry 2005;162:1483-1493
13. Gardner E. What We Have Learned about Addiction from Animal Models of Drug Self-Administration.The American Journal on Addictions 2000;9:285–313
14. Krashin D, Murinova N, Ballantyne J. Management of Pain With Comorbid substance abuse. Curr Psychiatry Rep. 2012;14:462-8.
15. DuPont R, Gold M. Comorbidity and "self-medication". J Addict Dis 2007;26(Suppl 1):13-23
16. Prescription Opioid-related Deaths Increased 114 Percent from 2001 to 2005, Treatment Admissions Up 74 Percent in Similar Period;Young Adults Hardest Hit http://www.ondcp.gov/news/press09/052009.html retrieved Oct.1,2009
17. Steven D. Passik, PhD* and Kenneth L. Kirsh, PhD † Fear and Loathing in the Pain Clinic Pain Medicine 2006;4:363–364
18. Goldenbaum D, Christopher M, Rollin M, Gallagher R, Fishman, S. Physicians Charged with Opioid Analgesic-Prescribing Offenses. Pain Medicine 2008;9:737-747.
19. Model Policy for the Use of Controlled. Substances for the Treatment of Pain Federation of State Medical Boards of the United States,2004; Retrieved Sept15,2009 from http://www.fsmb.org/pdf/2004_grpol_Controlled_Substances.pdf
20. Balancing Clinical and Risk Management Considerations for Chronic Pain Patients on Opioid Therapy http://www.aafp.org/online/etc/medialib/aafp_org/documents
    /news_pubs/mono/painmono/chronicpain.Par.0001.File.tmp/painmono.pdf retrieved Oct 1, 2009
21. Savage S, Johanson RD, Covington E, Schnoll S, Heit H, Gilson A. Definitions related to the medical use of opioids: Evolution towards universal agreement. Journal of Pain Symptom Management 2003;26:655
22. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000
23. Brady K, Sinha R.Co-Occurring Mental and Substance Use Disorders: The Neurobiological Effects of Chronic Stress . Am J Psychiatry 2005;162:1483-1493
24. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed., text revision. Washington DC: American Psychiatric Association, 2013.
25. Porrino L, Lyons D, Smith H, Daunais J, Nader M. Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains.Journal of Neuroscience 2004;24:3554-3562.
26. Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the "dark side" of drug addiction. Nat Neurosci 2005; 8:1442–1444
27. Koob, G. Neuroadaptive mechanisms of addiction: Studies on the extended amygdala. European Neuropsychopharmacology 2003; 13:6
28. Gardner E .The neurobiology and genetics of addiction: implications of the reward deficiency syndrome for therapeutic strategies in chemical dependency. In: Elster J, ed. Addiction: entries and exits. New York: Russell Sage Foundation, 1999:57-119
29. Humphreys K, Wing S, McCarty D, Chappel J, Gallant L, Haberle B. et al Self-help organizations for alcohol and drug problems: Toward evidence-based practice and policy. Journal of Substance Abuse Treatment 2004;26:151-158
30. Comings D, Blum K, Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res. 2000; 126:325-41
31. Gorski, T., and Miller, M. Staying Sober - A Guide for Relapse Prevention. Independence, Missouri: Herald House/Independence Press, 1986
32. Institute of Drug Abuse, Principles of Drug Addiction Treatment. www.nida.nih.gov/podat/podatindex.html. Retrieved on August 19, 2009
33. Gardner E. Pain and chemical dependency. chapter 51, pain management and the so called risk of addiction: a neurobiological perspective 2008 p 432., pain and chemical dependency book p 432.
34. Miotto K, Kaufman A, Kong A, Jun G, Schwartz J. Managing co-occurring substance use and pain disorders. Psychiatr Clin North Am. 2012;35:393-409.
35. Institute of Drug Abuse, Principles of Drug Addiction Treatment. www.nida.nih.gov/podat/podatindex.html. Retrieved on August 19, 2009
36. Samaha A, Robinson T. Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci 2005;26:82-87
37. Kaiko et al. pharmacokinetic-pharmicodynamic relationships of controlled release oxycodone Clin Pharmacy Therapeutics 1996; 59:52-61
38. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med 2005;6:432-442
39. Akbik H,Butler S,Budman S, Fernandez K Validation and Clinical Application of the Screener and Opioid Assessment for Patients with Pain. Journal of pain and symptom management 2006;32:287–293
40. Kahan M, Srivastava A, Wilson L, et al. Misuse of and dependence on opioids: study of chronic pain patients. Can Fam Physician 2006;52:1081–1087
41. Hwang CS, Chang HY, Alexander GC. Impact of abuse-deterrent oxycontin on prescription opioid utilization. Pharmacoepidermiol Drug Saf. 2014 Nov 13.
42. Myrick H, Malcolm R, Taylor B, LaRowe S. Modafinil: reclinical, clinical, and post_marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry 2004;16:101-109
43. Mallinoff H, Barkin R, Wilson G. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. 2005 Am J Ther 12:379-384
44. Walsh S and Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic, Drug Alcohol Depend 2003;70:S13–S27
45. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: A review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician. 2012;15(3 Suppl):ES67-92.
46. http://www.firstlab.com/newsletters/newsletterdocs/etgetsbiomarkers033009.pdf Retrieved Oct 3, 2009
47. Dupont R, Goldberger B, Gold M, (2009). Clinical and legal considerations in drug testing. Principles of addiction medicine (4th addition, Chapter 110, pp.1499-1507) Philadelphia: Lippincott Williams &Wilkins.
48. Trescot A, Boswell M, Sairam A , Opioid Guidelines in the Management of Chronic Non-Cancer Pain Pain Physician 2006;9:1-40
49. Weaver M, Schnoll S, Addiction Issues in Prescribing Opioids for Chronic Nonmalignant Pain. J Addict Med 2007;1: 2-10
50. Passik S, Kirsh K,.Managing Pain in Patients With Aberrant Drug-Taking Behaviors J Support Oncol 2005;3:83–86
51. Kahan M, Srivastava A, Wilson L, et al. Misuse of and dependence on opioids: study of chronic pain patients. Can Fam Physician 2006;52:1081–1087
52. Devulder J, Richarz U, Nataraja S. Impact of long-term use of opioids on quality of life in patients with chronic nonmalignant pain. Curr Med Res Opin 2005;21:1555–68
53. Sullivan M, Edlund M, Steffick D, et al. Regular use of prescribed opioids: association with common psychiatric disorders. Pain 2005;119:95–103
54. Chou R, Fanciullo G, Fine P, Adler J, Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Non Cancer Pain The Journal of Pain 2009;10:113-130.