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9 Articles in Volume 15, Issue #5
Case History of Chronic Migraine: Update 2015
Chronic Pain Patients Who Fail Standard Treatment: Now What?
Diagnosing Fibromyalgia
Gabapentin Abuse
Microglial Modulators: A New Therapeutic Class
Myofascial Pain: What is the Best Treatment?
Pain and Aging
Spirituality & Healing Touch
Tables Turn on Pain Psychologist

Chronic Pain Patients Who Fail Standard Treatment: Now What?

There is a group of severe and chronic pain patients who do not get adequate pain relief despite a clinical regimen that includes non-opioid medications and a daily opioid dosage of 100 mg or more morphine equivalents (MEQ).1-4

Until recently, most of these patients (hereafter called treatment failures) could only be effectively treated by raising the opioid dosage. This often resulted in the administration of high and ultra-high opioid dosages to obtain enough pain relief to enable patients to physically and mentally function, carry out activities of daily living, and attain an acceptable quality of life.

Today, these same treatment goals now can be achieved without resorting to extremely high or ultra-high opioid dosages. Thanks to a new understanding of pain centralization, opioid metabolism, genetic defects, and hormonal relationships to pain control, successful pain relief can usually be achieved, even for these previously considered treatment failures.5-8

Essential Testing

New and essential laboratory testing is now available to aid the development and administration of effective treatment strategies for treatment failures. I previously outlined these diagnostic tests in the first of this 2-part series.1 Diagnostic tests include genetic assays, opioid serum levels, neuroinflammatory biomarkers, and hormone profiles (Table 1).

Described here are the strategies used by the author to treat patients who fail 100 mg per day, or more, of MEQ and have 1 of the 4 basic causes of treatment failure (Figure 1). The strategies described have two primary goals: provide enough pain relief to function and carry on activities of daily living, and keep opioid dosages below an ultra-high level.

Treatment Strategy #1: Non-Oral Opioids

Opioid malabsorption is defined as the inability to transport opioids from within the intestinal lumen into the serum.6 When present, it may be a cause of treatment failure. Opioid malabsorption is more common than generally recognized. The symptom hallmark is poor relief with oral opioids. Every patient who fails to get relief with 100 mg or more of MEQ should be evaluated for opioid malabsorption. Common symptoms of malabsorption include bloating, steatorrhea, nausea, and undigested food or medication in stools.

The most common cause of opioid malabsorption is the presence of a gastrointestinal disorder such as diabetic gastroparesis, chronic pancreatitis, and/or chronic disease; as well as multiple abdominal surgeries or adhesions that may disturb the neuronal innervation of the intestine. Other causes include traumatic brain and/or neck injury, because proper function of the vagus nerve is critical for intestinal absorption. Lower spine surgery or injury, hormonal deficiencies, and autoimmune disease also may cause opioid malabsorption. Patients with opioid malabsorption may show low opioid serum levels.

An injectable challenge with an opioid, such as hydromorphone, morphine, or meperidine, will help confirm the diagnosis and help select an effective opioid for treatment.6 It is also important to point out that opioid malabsorption is likely increasing in incidence and prevalence in the population, due in part to the increasing incidence of diabetes, bariatric surgery, and autoimmune disease, among other causes of malabsorption.

Treatment of Opioid Malabsorption

If opioids are not being properly absorbed via the gut, it is important for the clinician to find another route of administration. Several non-oral formulations are commercially available (Table 2). These include transdermal, transmucosal, and injectable opioids. Naturally the underlying cause of malabsorption should be treated, if possible.

Case Example: Gastrointestinal Disorder

A 57-year-old woman has Crohn’s disease and has undergone 28 abdominal/pelvic/rectal surgeries. She had a significant small bowel resection, as well as a total colectomy with rectum removal. She evacuates through an intestinal portal with a syringe. Over several years she developed, in addition to severe abdominal pain, lower spine and fibromyalgia-type pains.

She was referred to my practice and was taking these oral opioids each day: hydromorphone 48 mg; hydrocodone 30 mg; and codeine 60 mg. The patient stated that only oral hydromorphone provided any pain relief, but she was still bed- and house-bound most days each week. She was switched to a regimen of transdermal fentanyl (50 mcg every other day) and injectable hydromorphone (5 to 8 mg) for breakthrough pain. This regimen allowed her to physically and mentally function each day and no longer be bed or house bound.

The problem of opioid malabsorption in this patient had gone unrecognized by multiple practitioners and institutions, even though the severity of her intestinal problem was quite obvious. A history of poor pain relief with oral opioids and the presence of an abdominal or pelvic disorder should always raise a suspicion of opioid malabsorption. This includes previous abdominal or pelvic surgeries, which may leave residual adhesions and/or neuropathies.

Case Example: Traumatic Brain Injury, Spine Degeneration, and Hormonal Deficiencies

A 44-year-old woman sustained a severe fall, which resulted in a concussion and cervical spinal injury. Over a 15-year period she saw numerous physicians and pain specialists who prescribed a variety of oral opioids and non-opioid measures.

She was referred to my practice because all oral opioids had “stopped working,” and she had lost 30 to 40 pounds. She was too weak to ambulate and was bed-bound. At her initial evaluation she had a blood pressure of 87/61 mm/Hg, was emaciated, and had pigmented lesions over her upper trunk, where open, inflammatory skin lesions had developed.

A hormone profile showed pituitary-adrenal insufficiency with a serum adrenocorticotropin (ACTH) level of less than 5 pg/mL (normal 6-50) and cortisol of 1.7 mcg/dL (normal 4.0-22.0). Her oral opioid dosage was 120 mg of hydrocodone each day; however, that regimen provided minimal pain relief for only about 1 hour.

A subcutaneous hydromorphone challenge of 2 mg provided her with immediate pain relief. The patient was started on transdermal fentanyl, 50 mcg every other day, and injectable hydromorphone 2 mg for breakthrough pain. Hydrocortisone was started at 15 mg a day. Within 10 days, her pain was significantly reduced, and she could ambulate and care for herself.

Traumatic brain injury and/or cervical neck trauma may cause autonomic dysfunction due to vagus nerve injury. Proper autonomic neural function is critical for intestinal absorption of opioids. Hormone deficiencies, such as was found in this patient, may also contribute to malabsorption.

Strategy #2: Genetic Opioid Compatibility

Genetic opioid incompatibility is defined as the presence of one or more genetic metabolic defects that prevents the normal metabolism and effectiveness of an opioid. Administration of an opioid that is incompatible with a genetic defect may be totally ineffective or require the opioid dosage to be very high.8 Several genetic tests are now commercially available to pain practitioners. The assays are generally classified as pharmacokinetic or pharmacodynamic. Pharmacokinetic assays are cytochrome P 450 (CYP450) enzymes that are principally found in the intestine and liver.9-11

Patients who require a daily opioid dosage of 100 mg or more of MEQ may have one or more CYP450 abnormalities or defects, since they are involved in the speed of metabolism and the conversion to metabolites.10,12 Pharmacodynamic assays measure the sensitivity or affinity for receptor binding or enzyme efficiency. The two most available pharmacodynamic assays are mu opioid receptor 1 (OPR1) binding and catecholamine-O-methyltransference (COMT). Early clinical experience suggests that opioid requirements are higher in patients with intermediate or low sensitivity to OPR1 and those with a high or moderate sensitivity to COMT.

The best studied CYP450 enzymatic defect is the 2D6 enzyme.8-10,13 This enzyme helps metabolize codeine, tramadol, oxycodone, and hydrocodone. If a patient has a 2D6 defect, avoid these opioids. There are 4 opioids that do not use the CYP450 system for metabolism: hydromorphone, morphine, tapentadol, and levorphanol (Table 3). The most plentiful CYP450 enzyme in the body is 3A4.8,10 Fentanyl exclusively uses this enzyme for metabolism, so it may be effective when other opioids fail.8,10 The use of a stimulant such as dextroamphetamine, methylphenidate, or phentermine may reduce opioid needs in a patient who has high or intermediate COMT sensitivity.

Case Example: Multiple P450 Cytochrome and COMT Defect

A 42-year-old woman developed constant headaches following a bout of viral encephalitis. Multiple opioids, neuropathic agents, and triptans were not successful in keeping her functional and able to consistently avoid a bed- and home-bound state. Cytochrome P450 testing revealed the following enzymes to be defective, in that they were intermediate metabolizers: CYP 2D6, CYP 2C19, and CYP 2C9. In addition her COMT enzyme showed intermediate activity. Her pain and ability to function and avoid a bed/home-bound state was accomplished by prescribing 2 opioids that do not utilize the cytochrome P450 system as well as a weak adrenergic compound. At the time of this writing she uses morphine extended release 100 mg two times a day (bid); hydromorphone 4 to 8 mg for breakthrough pain; and phentermine 37.5 three times a day (tid).

Genetic testing has its best use in patients who fail standard treatment. In this case the patient had 3 CYP450 defects and an intermediate COMT sensitivity that may alter normal adrenergic metabolism. She is managed by opioids that do not require the CYP450 enzyme system plus a weak stimulant.

Case Example: Normal CYP450 3A4 and Fentanyl Effectiveness

A 44-year-old woman was referred to my practice with Chronic Regional Pain Syndrome of the right arm and chest wall. The initial injury was due to a breast implant that migrated into the chest wall muscle. Despite taking 120 mg of oxycodone a day plus a number of non-opioid medications, she was confined to her bed, debilitated, and non-functional. She claimed this dose of oxycodone provided minimal pain relief for only 1 to 2 hours. A genetic screen showed the following: CYP 2D6, intermediate; CYP 2C19, rapid metabolizer; CYP 3A4, normal; CYP 3A5 non-expressive; and COMT low activity.

She was prescribed this basic regimen: hydromorphone 16 to 32 mg, bid to 4 times a day (qid), and transmucosal fentanyl 200 mcg for breakthrough pain. She now claims good pain control and has been able to carry out activities of daily living.

Oxycodone is partially metabolized by CYP 2D6 and this patient was an intermediate metabolizer; thus, poor pain relief with oxycodone would be expected. Her genetic screen for CYP 3A4 was normal. She was able to attain good pain control with fentanyl, which utilizes CYP 3A4, and hydromorphone, which bypasses the CYP 450 system. Without genetic testing, the identification of a successful pain regimen would have taken considerable time, and trial and error.

Treatment Strategy #3: Hormone Therapy

Hormone therapy is defined here as replacement of a deficient hormone(s) or the administration of hormones that have neuroprotection or neuroregenerative properties. Hormone profiles, consisting of 6 to 8 hormones known to be critical for pain relief, 7,14 can now be commercially obtained (Table 4). For example, adrenal and gonadal hormones are necessary for proper receptor binding, neurotransmission, and maintenance of the blood brain barrier.14-20 I recommend that chronic pain patients who require more than 100 mg per day MEQ and do not achieve adequate pain relief have a hormone profile to assess pituitary, adrenal, gonadal, and thyroid function.

Adrenocorticotropin (ACTH) is a critical biomarker to assess pain severity and control.7 High serum levels indicate out-of-control pain and that the patient has an intact, well-functioning pituitary. A low serum ACTH level may indicate out-of-control pain that has exhausted pituitary reserves and may also signal possibly intrinsic, pituitary disease. The other hormones listed in Table 4, including cortisol, pregnenolone, and estradiol, should be replaced if they are found to be low in the serum. It is recommended that hormone deficiencies be corrected before significantly raising an opioid dose. Opioid dosages can almost always be lessened if hormone serum levels are first normalized. Early clinical reports indicate that the use of the neurohormones, oxytocin, and human chorionic gonadotropin, reduce the need for opioids. Short clinical trials with these hormones are recommended in failing patients.

Case Example: Pituitary-Adrenal Insufficiency

A 41-year-old woman with severe lumbar spine pain was referred to my office. The patient was on a combination of hydrocodone 10 mg, oxycodone 30 mg, and hydromorphone 4 mg (up to 4 times a day), which had failed to control her pain sufficient enough to allow her to mentally and physically function and carry out activities of daily living. She had previously undergone multiple epidural corticoid injections and surgery for herniated discs.

A hormone profile revealed the following serum hormones to be low: cortisol 1.6 mcg/dL (normal 4.0-22.0), pregnenolone <6 ng/dL (normal above 13), and ACTH <5 pg/mL (normal 6-50). The patient was maintained on essentially the same opioid dosage and she was started on pregnenolone 300 mg a day and hydrocortisone 5 mg bid. The latter was increased to 3 times a day after 1 month. Within 6 weeks the patient was able to function due to increased energy and pain control. Within 1 month, her cortisol and pregnenolone levels had returned to normal (14.6 mcg/dL and 219 ng/dL). Her ACTH rose to a low normal range (6 pg/mL).

Severe, constant pain as well as opioid drugs may reduce some hormone serum levels.7,21 Replacement of hormones may be essential for adequate pain control, because some hormones such as pregnenolone and cortisol are necessary for opioid receptor binding and other analgesic-related functions.14-20 It was not necessary to raise this patients daily opioid dosage in order to achieve pain relief.

Case Example: Multiple Hormone Deficiencies

A 50-year-old male was hit by a car while riding a bike. He required lumbar spine surgery and continuous opioid therapy after his surgery. He was referred to my office because a fentanyl transdermal patch (100 mcg) and hydromorphone (8 mg qid) did not adequately relieve his pain. He was very sensitive to touch, suggesting the presence of hyperalgesia. He could not ambulate well and required a wheel chair. He could not carry out activities of daily living.

A hormone profile revealed the following deficiencies: cortisol 2.8 ug/dL (normal 5.0-25-0); testosterone 105 ng/dL (normal 129-767); and pregnenolone <5 ng/dL (normal 13-28). His opioid regimen was held constant and he was started on the following hormones: pregnenolone 100 bid, medroxyprogesterone 10 mg bid, and testosterone topical cream 2% bid. Within 1 month he no longer needed a wheelchair to ambulate and he had enough pain control to function and resume his usual vocational activity as a computer consultant. He could easily tolerate touch and pressure indicating that hyperalgesia was gone. All hormone levels returned to normal within 60 days.

Patients who present on high-dose opioids that are not effective in controlling pain and/or associated with hyperalgesia should have a hormone profile. If hormone deficiencies are found, it is recommended that they first be replaced before opioids are rotated or the daily dosage increased.

Treatment Strategy #4: Microglia Modulation

Chronic pain patients who fail to achieve pain relief on 100 mg or more of MEQ should be assessed for microglia overstimulation and centralized pain.5,22-24 The centralization process is caused by over-activation of the microglia, which produces neuroinflammation, metabolic disturbances, and even cellular destruction.22-24 The most common clinical manifestations are constant pain, sleep interference, fatigue, depression, and over stimulation of the autonomic, sympathetic nervous system and pituitary-adrenal-gonadal axis.

The overstimulation of the autonomic, sympathetic nervous system may be perceived by the patient as anxiety, allodynia, muscle spasm, tremors, and nausea among other symptoms. Pain catastrophizing is not unusual—that is, magnification, rumination, and feelings of helplessness. The many and multiple clinical manifestations of centralized pain are appropriately and necessarily treated with antidepressants, neuropathic agents, muscle relaxants, anti-anxiety agents, sleep aids, and opioids. If the multiple manifestations of microglia overstimulation and pain centralization are not aggressively treated, the patient on opioids will invariably demand a higher and higher opioid dosage.

A major thrust in treating failing pain patients is to administer agents that modulate or suppress over-stimulated microglia cells and neuroinflammation. Although unclear at this time, many of the agents currently used to treat the clinical manifestations of centralized pain, including depression, anxiety, and muscle spasms, likely have some modulating effects on microglial cells.5,23 Some of the anti-inflammatory agents including the salicylates likely enter the central nervous system (CNS) and modulate microglia and neuroinflammation.

A new class of agents, which are beginning to be known as microglia modulators, are fast emerging as ancillary alternatives to opioids in patients with centralized pain (See June's Editor’s Memo). The potential efficacy of these agents have been initially identified in animal and in vitro studies.5 Microglia have a plethora of receptors and appear responsive to a surprising number and types of agents. The antibiotics, minocycline and clarithromycin, are most notable. Ketamine, naltrexone, and some hormones are known to bind and modulate microglia. Early clinical trials appear quite positive, and this author is finding that they are effective in many treatment failure patients and that they usually spare opioids (Table 5).

Case Example: Neurohormonal Therapy

A 50-year-old woman sustained a fall at age 19. She developed headaches after the fall, which had been occurring daily every since. Over the years, she developed overt rheumatoid arthritis and lumbar spine degeneration with constant pain. She was referred to my office taking 7,200 mcg per day of short-acting fentanyl formulations, but this regimen only sporadically controlled her pain. She was often bed- and house-bound most days each week. She had previously failed treatment with multiple long-acting opioids and non-opioid agents.

Rather than increase her opioid dosage she wanted to attempt hormonal therapy, because she had heard they were a new option for pain treatment. She was started on human chorionic gonadotropin (HCG) 250 units sublingual 1 to 2 times a day. Her opioid regimen was left intact. Within 6 weeks she began to have some pain free hours, reported more physical movement, and was able to leave home to shop and carry out social activities. She reported less depression and an increased ability to care for her family.

Several hormones, including HCG, have receptors on glia cells.25 The precise relationship between neurohormones and microglia, however, is unclear. Patients are now asking for opioid alternatives, including hormones. This patient was given a short open trial of HCG, which was associated with great clinical improvement and obviated the necessity to elevate her opioid dosage.

Case Example: Minocycline Administration

A 52-year-old female had two-thirds of her pituitary removed due to an adenoma and Cushing’s Disease. She developed severe, constant generalized truncal pain immediately after the surgery and was unable to function or care for herself. She was referred taking these opioid drugs on a daily basis: extended-release oxycodone 20 mg bid; extended-release morphine 40 mg a day, and oxycodone 15 mg qid. Her opioid regimen was kept intact but she was started on minocycline 100 mg bid. The patient felt immediate relief with this compound and has remained on it for approximately one year. She has remained on her oxycodone formulations, but has stopped taking the long-acting morphine. She is now able to care for herself and claims she has good pain relief and some quality of life.

Multiple in vitro studies have shown that minocycline suppresses microglia activity although the mechanism is unknown.5 It has not been effective in all patients but this patient experienced great relief. Further studies will be required, as there are, as of yet, no controlled, evidenced-based studies to help select the best agent.

Therapeutic Structure and Goals

Severe, chronic pain patients who complain of poor pain relief with a daily opioid dosage of 100 mg or more MEQ are almost always non-functional in varying degrees. They are usually reclusive, bed- or couch-bound, seldom leave home, and have few social or vocational contacts.2-5 Diet, hygiene, exercise, and intellectual pursuits such as reading may greatly diminish. Many patients need a caregiver or family member to look after their basic needs of life. Most have patronized numerous physicians, emergency rooms, mental health facilities, and pain treatment establishments to little avail.

The primary goal of pain management is to gain enough physiologic and mental function to independently carry on activities of daily living and acquire some quality of life. Secondary goals are to enhance nutrition and immunologic status, and regain social skills. Failing patients must be educated to not expect total cure or pain elimination and that life-time pain management will be the norm.

The four basic treatment strategies outlined here do not have to be independently pursued. Two or more can be simultaneously or sequentially administered.Treatment failure patients on opioids should not be labeled an addict, drug seeker, or mentally ill. Pejorative labels should be avoided until a clinical evaluation and diagnostic tests for opioid malabsorption, genetic defects, hormone deficiencies, microglia stimulation and neuroinflammation are done to determine a possible biologic cause of treatment failure.

In addition to prescribing diagnostic tests and therapeutic agents, it is critical to place the patient in a structured clinical, outpatient setting. One pain practitioner who has the authority to prescribe medication, laboratory tests, and set rules and limits should head the team who treats the patient. Regular clinic appointments at one location with routine clinical procedures should be in place. All ancillary treatment staff, families, and patients need to have a clear understanding of therapeutic goals. Above all, the patient and his or her family must clearly know that severe, chronic pain that has centralized is a disease process, much like diabetes, schizophrenia, or rheumatoid arthritis. It will likely last a life-time but be subject to good control and compatible with a good quality of life.


Until the recent past, about the only remedy to treat chronic pain patients who did not find adequate pain relief with an opioid dosage of 100 mg or more of MEQ was to raise the oral opioid dosage to high or ultra-high levels. Additionally, these patients were usually considered addicts, drug-seekers, unmotivated, or non-compliant because they simply failed standard treatment. New understanding and laboratory tests for neuroinflammation, opioid serum levels, genetic defects, and hormone deficiencies now provide a scientific foundation to evaluate and successfully treat the failing high-dose opioid patient.

Based on a 4-component evaluation, as outlined in this article, a treatment strategy can almost always be developed that provides enough pain relief for the failing patient to physiologically and mentally function well enough to carry out normal activities of daily living and achieve some quality of life. Although opioid dosages may have to be raised in some of these patients, seldom are ultra-high dosages needed. The treatment strategies described here are quite new and obviously will be refined, modified, and improved in the future. The good news is that diagnostic studies to determine the likely cause of treatment failure and strategies to deal with the cause can now be implemented and most failing patients can now be helped.

Last updated on: August 31, 2015
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