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10 Articles in Volume 15, Issue #1
Psoriatic Arthritis: Current Strategies for Diagnosis and Treatment
Traumatic Brain Injury: Evaluation, Treatment, and Rehabilitation
Pain Management in the Elderly: Treatment Considerations
9 Best Practices in Evaluating and Treating Pain in Primary Care
Rationale for Medical Management
New York State Enacts New Law to Prevent Drug Diversion
Editor's Memo: Acknowledging the Failure of Standard Pain Treatment
PPM Editorial Board Discusses Epidural Steroid Injections and Blindness
Ask the Expert: False Positive Amphetamine Urine Screens
Letters to the Editor: Pregnenolone, Acute Porphyria, Opioid Calculator, Arachnoiditis

Rationale for Medical Management

Many states are now requiring that physicians justify or provide a rationale for daily opioid dosages above a specified amount—usually described in morphine equivalents (MEQ). The “trigger” dosage usually ranges from 80 to 120 mg. Although not debating the merit of such regulations, the authors present a rationale for treating moderate to severe chronic pain with opioids.

In the last half decade, the field of pain management has been under tremendous pressure to re-evaluate best practices when it comes to prescribing opioid medications. First came a call to arms to recognize pain as the fifth vital sign and to tackle the under-treatment of pain.1 With improvements in pain management, however, came a rise in a number of adverse effects and outcomes, including unintentional overdose deaths, especially among women.2,3 Studies have shown that the higher the dose of opioid prescribed, the greater the risk of morbidity and mortality associated with the drug regimen.4-6 More recently, many people have come to believe that Medicare’s patient satisfaction surveys may significantly impact opioid abuse. The reimbursement model is based on patient pain scores—an issue that at times seems to overshadow withholding opioids in certain patients that have an elevated medical or mental health risk.7

Many states have established guidelines using daily opioid dosages to “trigger” certain events, such as a referral to a specialist or to revisit the treatment plan in detail. These opioid dosages are usually described in morphine equivalents (MEQ). These doses are also referred to as Morphine Milligram Equivalents (MME; nyc.gov), Morphine Equivalent Daily Dose (MEDD; palliative.org), MED (CMS), or Oral Morphine Equivalent (OME; cpsa.ab.ca) The “trigger” dosage usually ranges from 80 to 120 mg, or in some cases up to 200 mg of morphine equivalents.8

Although the public health benefit of these exact trigger levels may be debatable, they are now a growing reality facing clinicians, pain patients, and pharmacists alike. Washington State was one of the first states to build dosing triggers into their guidelines, and to call for doctors to refer to pain management specialists when daily doses reaches 120 mg MEQ.9 According to the Washington State guidelines, “The hallmark of the guideline is a recommendation to not prescribe more than an average daily MEQ of 120 mg without either the patient demonstrating improvement in function and pain or first obtaining a consultation from a pain management expert.”

The Ohio State Medical Board has also issued new guidelines with a cut-off of 80 mg/d.10 These guidelines use 80 mg MEQ as a “trigger threshold,” requiring the clinician to “press pause” and re-evaluate how to optimize therapy and ensure patient safety. Ohio took this approach in part because the odds of an overdose are significantly higher above that dose. The state also believes that the “pause offers a good opportunity for the prescriber to consider potential adverse effects of long-term opioid therapy.”10

This article offers basic rationale for clinicians when prescribing opioid analgesics above the trigger MEQ.

Rationale for Dosing

There are a number of reasons that patients may require higher doses of analgesics, including disease progression, increased activity, comorbid psychiatric disease, failure of conservative and non-opioid therapy, and under-dosing of opioids. Most experts agree that what drives higher doses in the chronic pain patient is inadequate pain relief and poor functioning. Therefore, the core rationale for opioid dosage escalation above the standard level is based on improving the patient’s pain, quality of life, and functionality while minimizing the adverse effects and clinical manifestations of uncontrolled pain.

Often missing in the debate over opioids is the negative consequences of uncontrolled pain. Uncontrolled pain is detrimental from both a physical and mental standpoint. It impairs many basic and instinctive physiologic functions including sleep, metabolism, intellectual processing, and hormonal balance. It impairs muscular movement, which additionally interferes with activities of daily living. This may be manifested by immobility, reclusiveness, and inability to dress, work, or care for family. Each of these adverse effects should be queried or elicited during a comprehensive patient history.

Uncontrolled pain causes hyperarousal of the sympathetic nervous and endocrine systems, which may lead to hypertension, tachycardia, hyperhidrosis, vasoconstriction, and the metabolic consequences of excessive cortisol release. In the author’s experience (FT), uncontrolled pain may elevate (and can later deplete) serum hormone levels such as corticotropin (ACTH), cortisol, and pregnenolone.11

Physical Examination

A patient who requires higher doses of opioids may have been seen by multiple physicians and have undergone a battery of tests. Unfortunately, it is these authors’ experience that all too often patients will describe their experience with these clinicians as suboptimal, with little to no physical examination performed (“…they never even touched me…”). However, a physical, hands-on examination cannot be skipped.

The physical examination of patients with intractable pain will usually reveal abnormalities consistent with neurological or musculoskeletal dysfunction. Included in this hands-on examination should be an assessment for muscle guarding or muscular spasms, joint contractions, and especially for neurological deficits including sensory (thermal or pinprick) hypo- or hyperesthesia, motor/muscle weakness, hyperreflexia (including assessment for positive clonus and Hoffman’s reflux), fine motor coordination, memory and even cranial nerve function.

Chronic, non-operable, spinal pain disorders are probably the most common conditions that require high-dose opioids.12 Arthritic and myofascial conditions, neuropathic pain, and headaches are other common causes. These conditions are almost always associated with inflammation and neurologic impairment. From a musculoskeletal standpoint, contractures and hypertrophy of joints may occur with potential physical deformities, asymmetry of musculature, leaning, scoliosis, impaired gait, and limitations of limb extension. Other than hyperalgesia, some central pain conditions such as fibromyalgia, migraine, phantom limb pain, and traumatic brain injury may show few, if any, physical signs except those caused by excess sympathetic discharge.

Clinicians should document in the medical record the trials and exact causes of failure or contraindication of non-opioid therapies (tolerability, adverse events, comorbid hepatic/renal issues, bleeding risk, etc), especially in the face of progressively escalating doses of opioids.

Diagnostic Tests

Unfortunately, even our greatest scientists have not developed an objective pain assessment tool (ie, a “painometer”). Diagnostic testing may not have a direct correlation with pain severity, but can help support a rationale for using higher daily opioid dosages. X-ray, MRI, and electro-diagnostic assessments establish that a pathologic disease process is present and potentially the cause of severe pain. Inflammatory markers, such as the erythrocyte sedimentation rate and C-reactive protein, document that an inflammatory process is present.13

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor binding profiles of opioids.14

However, altered opioid metabolism may also influence the efficacy and tolerability of opioid therapy, and several factors contributing to this metabolic variability have been identified. The risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease).14

Hence laboratory diagnostic testing may support the need for higher doses of opioids. Based on metabolism or genetic factors mentioned above, blood and urine tests in chronic pain patients may show variable and potentially inadequate opioid concentrations. For example, a low level of morphine under about 10 to 20 ng/ml in blood suggests too little opioid is available to provide therapeutic benefit. Most opioids are metabolized via the liver by one or more of the cytochrome P 450 (CYP) isozymes—the exceptions include hydromorphone, morphine, oxymorphone, levorphanol, and tapentadol. Genetic testing of the CYP system can identify a patient with a defective enzyme system who may require a higher-
than-normal opioid dose or a switch to another opioid that is not metabolized by that pathway.

Methadone is particularly an issue because blood levels don’t necessarily correlate to dose since the half-life of methadone can vary from one individual to the next, ranging from 15 to 150 hours. Moreover, drug-drug interactions can occur in a patient who is a poor CYP2B6 metabolizer. Studies have shown that these patients will have poor analgesia with predictable methadone blood levels, accumulation of the s isoform, and significant widening of the QTc interval even with low blood levels that correlate to methadone doses less than or equal to 80 MEQ’s. Lastly, the complexity for converting methadone to an MEQ is yet another issue that has not been universally agreed upon by experts.15

To complicate this even further, aside from the issues outlined herein, drug-drug and drug-disease interactions can essentially negate any presumed MEQ for several opioids. Oral morphine for example is not expected to be affected by CYP450 enzymes because it undergoes phase II metabolism only; however blood levels could be reduced by greater than 50% in patients who concurrently receive potent p-glycoprotein (pGP) inducers; as is the case with rifampin, a potent CYP34A inducer that also induces pGP.16

Aberrant Behaviors

Every patient who is being considered for opioid therapy needs to undergo a risk assessment protocol. We have included Heit and Gourlay’s Universal Precautions as an excellent example (Table 1).17,18 A patient who has demonstrated aberrant, inappropriate, and/or illegal behavior is at a high risk for abuse, diversion, or overdose while taking opioids. Table 2 lists some common aberrant behaviors. An absence of these behaviors should be documented in the medical record of a patient who requires high-dose opioids. A current print-out of a state prescription profile, for example Prescription Monitoring Programs, can support the absence of “Doctor Shopping.” In addition, we believe that clinicians need to document patient adherence to an opioid treatment agreement, which mandates compliance with receiving opioid prescriptions from a single physician and single pharmacy.

Documentation Procedure

We recommend a systematic method and approach to establish the rationale for an opioid dosage above a trigger level. We believe documentation is critical especially when a daily opioid dosage is near the trigger point, and certainly to document the rationale or justification in writing when prescribing an opioid above the trigger level.

While some high dose opioid prescribers may disagree with this approach, we call attention to the fact that those patients who require more than 80 mg of MEQ may likely have to take opioids for life. It seems reasonable to us that a sound documentation of the need for high-dose opioids should be firmly established. For example, every patient doesn’t need to have had an MRI, hormone testing, or show signs of excess sympathetic discharge. What we think is essential is that there is a clinical picture of inadequate response to non-opioids or non-medical therapies, standard opioid dosages, one or more medical contraindications to non-opioids, and continuing adverse effects of severe pain.

Patient and Family Claims

Intuitively, the most common reason to escalate opioid doses above 80 or 120 mg MEQ is that the patient needs it for pain control. It is critical that the person be an established, compliant patient who demonstrates no aberrant behavior. Family input and involvement in making a decision to go above 80 mg a day is highly desirable, but not an absolute requirement, because many severe pain patients have little in the way of family or social support.

Opioid Equivalents and Conversion Calculators

We recommend the use of the PPM Opioid Calculator for calculating MEQs.19 Although there is no “standard” maximal dose of morphine or similar opioids, the literature is replete with trials documenting ranges of morphine equivalents and adjuvant therapies for the management of chronic pain patients. While not always consistent, a variety of articles are available describing the equianalgesic dosing and relative potency of opioids compared to morphine.

Depending on the opioid conversion resource used, 80 mg of morphine (a common trigger/limit) may be equivalent in potency to 8 hydrocodone 10-mg tablets per day.19 Hydrocodone is the most widely used opioid by volume, and dosages prescribed by primary care physicians usually remain below this level. Although levels of morphine above 80 mg may be considered high by many observers, trials of chronic pain patients would suggest that opioid doses are frequently titrated to higher doses. Regulators, legislators, public interest groups, and healthcare practitioners remain focused on safety, and therefore we enter into a new era of having to document and justify a rationale for prescribing opioids at these higher trigger levels.

Summary

It is not our intent to discuss or debate the merit of “trigger” levels of opioids. We are also quite aware that a single dosage level of morphine equivalents is a somewhat subjective measure that does not account for weight, gender, drug interactions, or genetic predisposition of individual patients. Chronic pain clinicians have long recognized that certain patients are opioid non-responders at low doses, and that higher doses will often be required—one size does not fit all. States need to consider this when establishing trigger dosages.

Pain practitioners should recognize and document that pain that requires a moderate to high opioid dosage will produce effects on the physiologic, hormonal, and sympathetic nervous systems that can be identified. Also, diagnostic tests are available that can help validate the presence of a pathologic condition that is capable of producing pain of such severity that it will require moderate to high opioid dosages.

The method to develop and document the need for high opioid dosages recommended here is a “work in progress.” Other measures can be added, and the authors invite suggestions to our recommendations. The primary goal in our recommendations is to provide an urgent response to the wave of “trigger” dose levels that states are rapidly adopting. Already, due to trigger guidelines and regulations, some patients are crossing state lines to seek care and some physicians are no longer willing to prescribe any opioids to the legitimate patient. These events risk needless suffering in a population of patients that are undertreated at baseline.

Last updated on: June 15, 2015

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