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10 Articles in Volume 17, Issue #6
A Plea for Proper Opioid Tapering
Centers of Excellence in Pain Management: Past, Present, and Future Trends
Comorbid Pain and Childhood Obesity
Discussing Migraine With Your Patients: A Common Sense Guide for Clinicians
Justification of Morphine Equivalent Opioid Dosage Above 90 mg
Letters to the Editor: Dependence vs Addiction, Opioid Metabolism
Opioid Rotation From Opana ER Following FDA Call for Removal
Psoriatic Arthritis: Established, Newer, and Emerging Therapies
Sleep-Wake Disorders and Chronic Pain: Reciprocal and Interactive Effects
What are Nav1.7 inhibitors and how are they used in the treatment of neuropathic pain?

Justification of Morphine Equivalent Opioid Dosage Above 90 mg

One team’s rationale for justifying prescribing higher dosages of opioids.

It is recognized that some patients with severe chronic pain require opioid dosages over 90 morphine milligram equivalents (MME) a day.1 The Centers for Disease Control and Prevention (CDC) has stated in its opioid prescribing guidelines that physicians should evaluate and carefully justify the rationale for prescribing above this level.2 California, where we practice, also has written guidelines that require justification for a daily opioid dosage above 80 MME.

The CDC guidelines relate to adults with noncancer pain and those who are not receiving palliative or end-of-life care. The guidelines are intended for use by clinicians evaluating new “opioid-naïve” patients and for non-pain specialists using chronic opioid therapy to treat patients in pain, including those who already take an opioid dosage above the 90 MME. The CDC defines chronic pain as 3 months or more of persistent pain or pain past the time of normal healing in an outpatient setting.

We are independent medical practitioners who dedicate a portion of our time to the management of intractable pain patients. We have formed a network of physicians and regularly meet to review cases and improve our procedures and protocols to better care for these difficult patients. At this time, we have not found any instructions from federal or state agencies on how a physician should justify a daily opioid dosage above 80 to 90 MME, so we have developed an evaluation protocol to provide such justification. This article provides details about our protocol.

Editor’s Note: the protocol presented here represents the authors’ opinions, and not necessarily those of PPM or the publisher. No prospective study has been carried out to evaluate the risk of patients who are screened using this tool. Future investigation, therefore, is warranted.


Patients evaluated using our protocol are patients with intractable pain who have failed multiple nonopioid measures and have been titrated up to an opioid dosage greater than 90 MME prior to referral to our practice (Table 1).

The basics of the evaluation consist of history, physical examination, determination of family involvement (defined here as a close family member(s) who is knowledgeable and participating in the ongoing care process), serum testing for inflammatory markers and hormone abnormalities, and review of medical records and diagnostic tests, including magnetic resonance imaging (MRI), x-rays, etc. Some initial risk assessment for abuse of opioids and other medications is recommended. We use the Opioid Risk Tool (ORT), CAGE questionnaire on alcohol use, and SOAPP (Screener and Opioid Assessment for Patients with Pain) scales.

We consider there to be selected pain patients who can’t be treated with opioids, regardless of dosage. These include people with opioid-use disorder, patients who can’t or won’t provide medical records that document past treatments, and patients who have psychiatric disease, including anxiety, depression, and bipolar disorder, who are unable to mentally process medical instruction, safely protect medication, and provide self-care. We do not consider mental impairments to be an absolute contradiction to opioid therapy, but we do require a caretaker, such as a nurse or trusted family member, to control, protect, and administer medication in such cases.

Intrinsic to our evaluation is the determination of medical necessity for high-dose opioids to prevent the complications of severe, undertreated pain. In addition, communication between clinicians and patients is vital, especially to convey information about the risks and benefits of opioid therapy and ensure an understanding of the goals of therapy—including improving the patient’s quality of life and functioning.

Patient Record

We recommend that a summary form be used to compile the reasons supporting the decision to exceed 90 MME (Table 2). The reasons and rationale for exceeding 90 MME are multiple, and they should be compiled as a compendium that can be placed in the patient’s chart and submitted to concerned parties, including regulators and third-party payors, as needed. Every component listed on our example summary form need not be present to justify a 90 MME.

Physical Examination

All the major underlying causes of pain severe enough to require a high dosage of opioids will exhibit some physical signs. Diseases such as arachnoiditis, reflex sympathetic dystrophy/chronic regional pain syndrome, and genetic connective tissue disease will show structural anatomic damage and/or physiologic impairment of nerves, muscle, bones, tendons, or joints.3

MRI is necessary to diagnose adhesive arachnoiditis in the lumbar spine.4 MRIs also will show a variety of other pathologic painful abnormalities that may be present in and around the spine. Plain x-rays still may be useful, particularly for joint and spine abnormalities in genetic and metabolic diseases such as kyphoscoliosis, sickle cell anemia, Ehlers-Danlos, and Marfan syndrome. Intestinal x-rays may be necessary to diagnose painful abdominal and pelvic conditions such as Crohn’s disease, intestinal obstruction, and abdominal or pelvic adhesions. A variety of electrodiagnostic tests are available to complement the electroencephalogram and electromyogram.5 These provide evidence of abnormal nerve conduction due to injury or disease.

Severe, chronic, painful diseases also may manifest in abnormal reflexes, posture, balance, ambulation, and extremity range of motion. If structural damage is grossly evident, we recommend taking a photograph for the patient’s record.

Since the patient is on an opioid and most likely other medications, an assessment of alertness, vision, speech, and mental acuity is necessary to document drug tolerance and ability to safely ambulate and, perhaps, operate a motor vehicle. Mental capability must be assessed as part of the physical examination.

If a patient’s pain is not adequately controlled, he or she will likely show some evidence of excess sympathetic discharge. Physical signs of excess sympathetic discharge include hypertension, tachycardia, mydriasis, hyperhidrosis, hyperreflexia, and cold hands and feet due to vasoconstriction.

Curable and Centralized? Review of the Records

Although there are clinical instances when an opioid dosage of 90 MME or more may be temporarily required, these situations usually involve short-term trauma, injury, or surgery. Chronic, long-term administration of opioids over 90 MME requires that an incurable underlying disease exists, and this fact should be noted in the patient’s chart.

We believe it is essential to clinically determine if the patient has centralized his or her pain.3 The presence of centralized pain signifies the need for long-term, and possibly life-time, pain management. Pain centralization occurs when microglial cells are activated after severe, painful injury or disease, generating neuroinflammation.4

Centralization may lead to a cascade of symptoms, including constant pain, insomnia, depression, fatigue, endocrine changes, and autonomic nervous system hyperactivity. High-dose opioids as well as a number of other pharmaceutical agents may be needed to control centralized pain. Although the discovery and concept of centralization is relatively new, sophisticated pain practitioners should know that this is a critical implication for patients who require high-dose opioid therapy.

Both the underlying cause of pain and neuroinflammation may cause elevation of serum inflammatory markers.4 These include erythrocyte sedimentation rate, C-reactive protein, and cytokines such as interleukins and tumor necrosis factor. Myeloperoxidase and alpha-1-antitrypsin may be elevated in patients with neuroinflammatory conditions, but testing for these markers is available only in specialist laboratories.5

Pain severe enough to require 90 MME usually will alter some of the stress and healing hormones in the endocrine system.6 The following may be altered by severe, chronic pain: cortisol, adrenal corticotropin, dehydroepiandrosterone, pregnenolone, estradiol, progesterone, and testosterone.7 To help provide objective evidence to initiate opioid therapy or maintain an existing patient on an opioid dosage greater than 90 MME, we recommend obtaining a blood profile of inflammatory markers and hormones through a local commercial laboratory.

Failure of Previous Treatments

We endorse following the World Health Organization’s (WHO) 3-step therapeutic ladder approach to pain management.8 Step 1 is the use of nonpharmaceutical measures, such as physical exercise, bracing, and electromagnetic measures, as well as use of nonsteroidal anti-inflammatory agents. Step 2 is the addition of pharmacologic agents, such as antidepressants and anticonvulsants. Step 2 also may allow for the use of a weak opioid. These 2 steps must be attempted before potent opioid therapy is attempted.

All published guidelines call for some step-up approach beginning with alternative measures. The CDC guidelines state that “clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate.”

There are many excellent nonpharmacologic measures that are noted in Step 1 of the WHO pain management ladder, including physical manipulation, nutrition, electromagnetic energy administration, acupuncture, homeopathy, prolotherapy, and psychotherapy. Nonopioid pharmacologic analgesics include prescription and nonprescription agents, such as amino acids, botanicals, antiseizure drugs, antidepressants, anti-inflammatories, topicals, and hormones.

As noted above, the vast majority of the patients seen in our clinic have failed multiple nonopioid measures, nonopioid pharmacologic agents, and opioid dosages less than 90 MME.

As recommended by the current CDC guidelines, clinicians should evaluate risk factors for opioid-related harms periodically while managing patients on opioid therapy. This includes “incorporating a management plan to mitigate risk, including offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, or concurrent benzodiazepine use, are present.”

As part of the evaluation to determine if a dosage over 90 MME is medically necessary, a treatment plan should be developed. Note, some of these plans are outlined by guidelines from the CDC as well as the American Pain Society and other associations. A plan includes measures such as frequency of body fluid testing, psychiatric referral, or incorporating nonmedical modalities.

Family Involvement

A pain patient who requires a high dose of opioid obviously has a severe underlying cause of pain that likely will shorten life and incapacitate the patient at some point. This patient will, therefore, need support from family or friends. At the initial evaluation, family and/or friends can help validate the medical history and provide helpful suggestions for devising a high-dose opioid treatment plan.

Assessing Function and Genetic Factors

Assessing patient function is crucial. The prescriber needs to assess the patient’s function and whether the opioid dose has improved or impaired function. If function has improved, then the patient is benefiting from his current regimen. Of course, there are patients with “legitimate” syndromes in which improved function just is not possible, such as patients with advanced multiple sclerosis and paralysis.

Many practitioners, including us, believe that there are certain genetic variations that require a patient to take more opioids than usual for pain relief. For example, DNA testing might reveal a patient to have a cytochrome P450 variation in the 2D6 enzyme that may cause him or her to be a “slow” or “rapid” metabolizer. Some of these variations may necessitate extra opioid administration or a switch to an alternative opioid, such as morphine, hydromorphone, oxymorphone, tapentadol, or levorphanol, for the patient to achieve and maintain a high enough serum opioid level for pain relief.6

Opioid receptor binding affinity can now be assayed. A patient with low opioid binding affinity will require higher than normal opioid dosages for pain control. Some variations in the enzymatic systems in the central nervous system (CNS) may force a need for a higher than normal opioid dose. The enzymatic system most studied to date is catecholamine-o-methyltransferase. This enzyme is responsible for degrading the catecholamines, dopamine, norepinephrine, and epinephrine in the CNS. It is believed by some observers that too little or too much enzymatic activity will alter CNS catecholamine levels and necessitate a higher than normal opioid dosage.

Variations in neurotransmitter transport proteins are being tested. Although no evidence has been published yet showing that variations in the transport of neurotransmitters such as serotonin, dopamine, or gamma amino butyric acid may cause an increase in opioid dosage, variations in transport activity are now part of DNA genetic test panels that are available to pain practitioners.

Surveys of our intractable pain patients who require over 90 MME show that over 90% have 1 or more genetic variations.9 Although the finding of genetic variations among high-dose opioid patients doesn’t prove a cause and effect, the high prevalence of genetic variations in these individuals is highly suggestive. Genetic variation can be a component of a profile to justify a high opioid dose, but there is not enough scientific evidence to use genetic variation as the sole determinant for such dosing.

Complications and Medical Necessity

Medical necessity is the term applied when a specific treatment is needed to prevent complications of a disease, including premature death. Severe intractable pain has many complications that are extremely deleterious to the patient. Chronic severe pain is known to affect both white and gray matter in the CNS.10 It can cause adverse cardiovascular effects, such as hypertension and tachycardia, with their attendant infarction and stroke risks. Adrenal, gonadal, and pituitary suppression may occur, which lowers a variety of hormones that are involved in neuroprotection, neurogenesis, and anti-inflammatory processes. Severe pain may affect mobility, and mental functioning, and may prevent a patient from carrying out activities of daily living, such as diet, hygiene, and dressing.

Declarative Statement

An option that practitioners should consider is a written declaration of justification and medical necessity. This statement can be attached to a summary form or provided as a separate document. A simple example is, “I declare that an opioid dosage above 90 MME is justified and medically necessary to relieve pain and prevent its complications.” This is a physician’s opinion and not necessarily a legal opinion.

Second Opinions and Consultations

An option that primary care physicians should consider for patients who require doses greater than 90 MME is a second opinion or consultation. It is well recognized that few chronic pain patients need to take over 90 MME. In fact, the majority of patients with chronic pain function on much lower doses—about 40 to 60 MME (approximately 10 mg of opioid [hydrocodone or oxycodone] and 325 mg of acetaminophen) in 24 hours. It may be most helpful to obtain a second opinion or consultation about the need for a high opioid dosage.


Federal and state guidelines for opioid prescribing caution and warn physicians about the risks of prescribing a daily opioid dosage over 90 MME. Third-party payors often try to use these guidelines as a rationale to restrict payment for opioid dosages. Although federal and state guidelines do not restrict dosages above 90 MME, they call for a justification before prescribing above this level. To our knowledge, no federal or state guideline has published specific criteria or requirements for prescribing doses above 90 MME. We have developed a structured evaluation protocol to justify a daily opioid dosage over 90 MME. Historical, physical, and diagnostic information is collected and summarized on a single document that can be placed in the patient’s chart and submitted to regulatory officials and third-party payors.

In our experience, patients who legitimately require an MME greater than 90 are quite obvious, and it is easy to justify such dosing in these patients. They demonstrate physical and laboratory diagnostic evidence of both their underlying disease and exorbitant pain. Their underlying disease and severe pain hve led to pain centralization with constant pain, insomnia, fatigue, and abnormal serum inflammatory markers and hormone levels. These patients have attempted multiple nonpharmacologic measures, nonopioid pharmacologic drugs, and standard oral opioid dosages without obtaining adequate pain relief. We highly recommend the use of our evaluation protocol or a similar tool so that deserving patients will not be deprived of necessary and humane treatment.



Last updated on: August 16, 2017
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