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10 Articles in Volume 13, Issue #4
Traumatic Brain Injury
US Service Members With Polytrauma
Cancer Patient: Controlling The Pain
Pharmaceutical Treatment of the Cancer Pain Patient
Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics
How Do We Get Enough Physicians to Medically Manage The Difficult (High-dose Opioid) Pain Patient?
Ultra-high Dose Opioid Therapy: Uncommon and Declining, But Still Needed
Head Trauma: More Than A Headache
Ask the Expert May 2013
Letters to the Editor May 2013

Ultra-high Dose Opioid Therapy: Uncommon and Declining, But Still Needed

There is a small, but tragic, group of chronic pain patients who require high or ultra-high daily doses of opioids. We have previously defined high dose as 200 mg per day and ultra-high dose as 1,000 mg per day of morphine equivalents.1 On the surface, the use of high opioid doses may appear controversial, but on close examination of various state medical board regulations, and even proposals to change FDA opioid labeling,2 there is no attempt to restrict or deny the use of ultra-high dose opioid therapy in needy patients.3,4 In fact, leeway is made for this outlier group if there is documentation that standard dosages and modalities have failed. Put another way, no party wants to leave patients in severe pain and suffering because of dosage restrictions. They just don’t want “unneedy” or “illegitimate” patients to receive high-dose opioid therapy.

At the outset, I want to emphasize that no physician should attempt high, much less ultra-high, dose opioid therapy unless the physician is experienced with this form of therapy because it has potential risks and hazards—endocrine complications are essentially universal with high-dose opioid therapy. That said, I would like to encourage interested pain practitioners to learn to prescribe high and ultra-high opioid doses when they are indicated and necessary to save a patient from suffering a bed-bound existence, or early death. Every community needs such a physician to provide ultra-high dose opioid therapy so these uncommon but needy patients don’t have to endure unthinkable misery. Table 1, will help calculate which dosage group to apply to patients.

The goal of this article is two-fold: First, to describe some apparent trends and emphasize that current standards for opioid pain treatment are adequate to validate the need for ultra-high dose opioid therapy.3,5 The second goal is to lay out some of the methods and procedures I personally use to ensure efficacy, safety, and prevention of overdoses and diversion in patients who require ultra-high dosages of opioids.

Need for High Dose Is Declining

The need for ultra-high dose opioid therapy, based on referrals to my clinic and discussions with other pain practitioners, appears to be declining. There are three main reasons for this decline. First, in the not too distant past, too often pain treatment was delayed, which allowed peripheral pain to become centralized. More recently, early intervention with aggressive pain treatment after surgery, trauma, or illness has been one of the biggest factors in the reduction of chronic pain. Second, some practitioners preferentially prescribed the most potent opioids (such as fentanyl and oxycodone), which drove up tolerance to the pain-relieving effect of the opioid too rapidly. Better education about proper opioid prescribing has led to a decline in these practices. The third reason for the decline is that many non-opioid therapies have been developed that reduce the need for opioids. These include neuropathic agents, electromagnetic devices, spinal interventions with corticoid injections, and hormonal agents. For example, a patient who complains of severe pain today, in contrast to some years ago, will more likely be started on non-opioid measures that keep opioid dosages in a lower range.

Standards and Guidelines

In 1998, the Federation of State Medical Boards created and published model guidelines for the use of controlled substances for the treatment of pain.5 These guidelines, which are summarized in Table 2, have endured and they are as applicable today as in 1998. Although various states may have slight variations in standards and guidelines (as do some professional organizations), they don’t deviate much from the 1998 model.1,3 Physicians who prescribe ultra-high dose opioids must closely follow these guidelines.5

Why Ultra-high Dose Opioid Therapy Is Still Needed

There are some forms of pain—just as there are forms of conditions such as hypertension, diabetes, and schizophrenia—that are appropriately called malignant or catastrophic.6 These are the outliers from the norm. Patients with these tragic conditions, just as some pain patients, cannot survive and function without competent, caring help, and high dosages of medication. If left untreated, severe centralized intractable pain not only causes a total bed-bound suffering state, but may contribute to early death. The mechanisms of death in severe pain patients are known to include cardiac arrhythmia, malnutrition, adrenal failure, and sepsis.7 Sometimes pain patients are found dead in bed or on the toilet and are falsely diagnosed as an overdose death.

Unfortunately, patients who require ultra-high dose opioid therapy often have seen too many practitioners who have attempted too many treatments that have failed to help. Practitioners often are afraid of ultra-high dose opioid therapy, so they try all kinds of treatments that may be detrimental and brutal to the patient. For example, I have been referred patients with spine conditions who have received between 25 and 50 interventional corticoid procedures of which none provided more than a few hours or days of relief. Multiple spinal surgeries are sometimes attempted because practitioners don’t want to embark on ultra-high dose opioid therapy. A review of my last 15 referrals in preparation for this paper revealed that the number of prescription medicines taken by each patient ranged from 6 to 15. Polypharmacy is not a substitute for directed opioid therapy. A delay of ultra-high dose opioid therapy may result in a patient’s pain becoming uncontrolled, resulting in detrimental immunologic, hormonal, and neurologic damage.6

Each community, therefore, needs a subspecialist or a referral and evaluation mechanism to get these patients the help they need. For example, a primary care physician or interventionalist pain practitioner may wish to help follow an ultra-high dose opioid patient if there is a physician they can consult with who is familiar with ultra-high dose opioid care. The important point is not to ignore these patients just because they are complicated and need extraordinary long-term treatment.

Long-term Care And Monitoring

It is doubtful that ultra-high dose opioid patients can ever be opioid-free, unless cures are found for centralized pain. They can, however, develop a quality of life and function quite well. These patients will need to be seen and monitored regularly to determine that opioids are not impairing their quality of life. Simple tests to measure blood pressure, pulse rate, and observation of ambulation and alertness usually are sufficient at each visit. Too high of an opioid dosage lowers blood pressure and pulse rate and too low of a dose allows pain to raise the blood pressure and pulse rate.7

Families must be aware of treatment goals and expectations. Many of these patients have shortened life spans. Patients will also need to be in a health care network that includes other health care providers, such as a primary care or specialist physician. It is quite helpful to have a psychologist, social worker, or minister counsel these patients to help them accept their “fate” and to develop skills to enable them to live a happy and fulfilling life.

Who Needs Ultra-high Opioid Dosages?

These patients are uncommon and in my experience, probably do not constitute more than 1% of chronic pain patients. Based on referrals to my clinic, I have concluded that these patients have three characteristics:

  1. Constant pain and insomnia that have not responded to standard opioid dosages and other measures
  2. Pain is “centralized” with hormonal changes
  3. Patient has one or more genetic metabolic defects, which necessitate high dosages

Centralized pain is focused in the brain and may occur in patients who have had a brain injury such as stroke, trauma, or infection; those who have pain arising “de novo” such as fibromyalgia, vulvodynia, or interstitial cystitis; and those who have had a peripheral nerve injury that has produced glial cell inflammation in the spinal cord and brain. A clinical diagnosis of centralized pain is given when the patient has a history of constant pain and insomnia plus a majority of these signs and symptoms: episodes of allodynia and hyperalgesia, impairment of some mental functions, elevated blood pressure and pulse rate, and physical evidence of excess sympathetic discharge including hyperreflexia, cold extremities, hyperhidrosis, and mydriasis.

Personal Methods And Procedures

I have chosen to publish here some of my personal methods and procedures dealing with ultra-high dose opioid patients. Many of these are outside of the basic medical board guidelines. My goal is to give the best pain relief and care while minimizing risk of overdose, diversion, and toxic complications. Also, I find that many of the procedures are very helpful with third-party payors, because they are intended to document a need for high-dose opioids. My methods and procedures are not necessarily recommended, and are presented here for voluntary adoption if they fit your personal practice.

Documentation of Need

I use a four-component process to provide adequate documentation for ultra-high opioid dosages. All patients don’t exhibit all the criteria listed here, but this process provides enough facts to justify high opioid dosages.

History of Failure

First, a patient who legitimately needs high opioid dosages will likely have tried a litany of procedures, surgeries, and drugs over a considerable time period. This litany must be documented in the patient’s chart. Today’s legitimate high-dose candidate will invariably have attempted at least some of the following modalities: corticosteroid injections; operations; physical measures including acupuncture and psychotherapy; antidepressants; anti-inflammatories; neuropathic agents; topical agents; and weak opioids such as tramadol, codeine, and hydrocodone. I also attempt to acquire as many previous records as possible.

Family Validation
A legitimate ultra-high dose opioid patient doesn’t come in off the street alone demanding drugs. Patients ill enough with pain to require more than 1,000 mg per day of morphine equivalents will likely have family members pleading for help for their loved one. While patients are in treatment, family support may be essential for basic sustenance and assistance with activities of daily living.

Physical Evidence of Nerve Injury
Nerve injuries from trauma or disease, which are severe enough to require ultra-high opioid doses, will demonstrate some physical evidence. I find this true even for diseases that usually don’t show gross abnormalities, such as chronic headaches, fibromyalgia, and back pain. In my experience, all patients have physical abnormalities to the experienced eye. For example, contractures that limit “range of motion” and muscle groups that show structural asymmetry are commonplace in long-term, severe pain patients. Centralized pain patients will exhibit increases in blood pressure and pulse rate, as well as diaphoresis, cold extremities, and hyperactive reflexes. I take pictures of physical abnormalities routinely to help document the severity of pain.

Laboratory Abnormalities and Biomarkers of Severe Pain
Some laboratory tests now make the identification of severe pain more objective and less subjective. The majority of patients who require ultra-high opioid dosages will demonstrate one or more cytochrome P450 defects.8 Genetic diseases, particularly those with an autoimmune component, cause severe pain in adulthood and require ultra-high dose opioids. Malabsorption of opioids is unusual but does exist. Pain severe enough to require ultra-high opioid doses commonly demonstrates some biomarkers indicative of severe pain. These include abnormal pituitary-adrenal hormone abnormalities and/or inflammatory markers. Laboratory tests by themselves don’t justify or call for high dosages, but they support other clinical findings.

Declaration of Need
It is highly recommended that the physician who prescribes high or ultra-high dose opioids place a signed “declaration of need” in the patient’s chart. This gives all parties a clear message that the patient has been evaluated and there is abundant recognition that standard treatments and opioid dosages have not worked. A signed “declaration of need” shows “good faith” that an extraordinary treatment is necessary and not an afterthought.

Treatment Principles

Table 3 outlines the principles of treatment. The first principle of ultra-high dose opioid treatment is to find an opioid regimen that allows the patient to escape a bed/couch-bound existence and function by stopping useless medications and other measures. Patients should be routinely monitored with blood pressure, pulse rate, and visual observation for sedation and ambulation. Patients who are taking too much of an opioid will show depressed blood pressure and pulse rate.

Recording family reports of physical and mental functions, sedation, and pain relief are essential. Once stable, an opioid blood level should be taken when the patient is alert, functional, and with normal vital signs.9 Tolerance to a high opioid dosage is established when vital signs and physical functions are normal at the same time there is a significant opioid blood level.

I find that opioid dosages can almost always be reduced once a patient is stabilized, has good pain control, and has achieved homeostasis of adrenal-gonadal hormones. Abrupt discontinuation, rotation, or forced reduction in opioid dosage will almost always result in failure in that the patient will resort to benzodiazepines, carisoprodol, antidepressants, and even street drugs to compensate. Hence, the risk of overdose goes up. Opioid reduction, in my experience, is almost universal when it is done slowly and progressively with a treatment plan that patient, family, and practitioner agree to. Urine testing will need to be done periodically to ensure compliance with a high-dose regimen as well as eliminate any use of abusable drugs.

Treatments other than opioids will likely have to be directed at both the centralized and peripheral components of the pain. Standard peripheral treatments such as exercise, topical medications, and electromagnetic therapies are very much in order. Centralized pain may require stimulants, neuropathic agents, antidepressants, and sedatives for sleep. If the oral opioid dosage requires an inordinate number of pills, I consider a non-oral administration route such as sublingual, injection, or intrathecal.

Ultra-high opioids will invariably cause suppression of some hormones.10-12 The most common hormones to be suppressed are testosterone, pregnenolone, and cortisol.10,11 These will have to be replaced. Osteoporosis, depression, hyperalgesia, mental deterioration, and hyperlipidemia disorders may occur if hormone homeostasis is not maintained. Endocrine suppression is most problematic with long-acting and intrathecal opioids.10,12

Patients who require ultra-high opioid doses always have underlying causative factors and complications. They need to be in a care system that includes a primary care physician and possibly a specialist physician. Psychological and spiritual involvement is highly recommended.


A small and uncommon subset of chronic pain patients will need more than 1,000 mg of morphine equivalents per day. Due to early and aggressive pain treatment following injury, trauma, or surgery, as well as new treatment measures, the need for ultra-high opioid doses appears to be declining. There will, however, always be outliers from the norm. Patients who require ultra-high opioid doses can be identified by a history of standard opioid dose failure, family validation, physical examination, and laboratory evidence. Physicians who treat ultra-high opioid dose patients should make it a regular avocation. Rather than deny that these patients exist, all communities and pain practitioners should help develop a referral and treatment mechanism to care for these uncommon, but needy, persons.

Last updated on: October 28, 2014
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