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11 Articles in Volume 15, Issue #2
Chronic Headache Management: Outpatient Strategies
Magnesium Sulfate Helpful in Treatment of Acute Migraines
New Guide to Migraine Rx Garners Mixed Reviews
Pain Education Across VA Clinics
12 Classes Offered at VA Pain School
Practical Guide to the Safe Use of Methadone
Chronic Pain Patients Who Fail Standard Treatment
Balancing State Opioid Policies With Need for Access to Pain Therapies
New Mexico’s Approach to Improving Pain and Addiction Management
Editor's Memo: Prescription Opioid Abuse is Declining
Ask the Expert: Lupus and Suicidal Ideation

Chronic Pain Patients Who Fail Standard Treatment

One of the major unmet needs in pain management is the patient who is failing to find relief with standard chronic pain treatment. Part 1 of this 2-part series will describe the author’s protocol for the diagnosis and evaluation of patients who have failed standard pain regimens.

Patients who fail, or receive minimal relief from, standard pain treatment represent a unmet medical need.1 Despite receiving standard treatment for moderate-to-severe pain, as outlined by the World Health Organization, some patients are unable to adequately function, carry on activities of daily living, or have a decent quality of life. As a consequence, such patients often seek treatment alternatives, higher opioid dosages, and/or remain reclusive at home and in bed. A recent survey of 40 consecutive patients referred to the author due to failure of standard treatment, including potent opioids, found that the patients collectively had consulted 461 physicians, 172 pain specialists, 104 psychologists or psychiatrists, and 23 university centers without finding any sustained pain relief.2

Fortunately, new diagnostic tools that recently have become available to objectively study patients with chronic pain might help practitioners develop effective treatment strategies for these patients. Part 1 of this 2-part series will describe the author’s protocol for the diagnosis and evaluation of patients who have failed standard pain regimens and the therapeutic strategies he has used to help a great majority of them regain a better quality of life.

Although the diagnostic evaluation and treatment strategies presented here are in a very early stage of development and undoubtedly will improve, the need to address failing patients is urgent. Consequently, this report describes the author’s attempts to deal with this problem. Part 2 of this series will outline the treatment strategies that have been developed to assist them.

What Is Standard Treatment?

The long-standing standard of pain treatment is the 3-step analgesic ladder developed in 1982 and adopted in 1986 by the World Health Organization (WHO).3 Although originally adopted for cancer pain, and despite many new treatments, approaches, and suggestions to modify the 3-step ladder, it remains the standard treatment approach for treating chronic pain, including cancer-related pain.4 The WHO pain ladder (Figure 1) describes pain in terms of intensity and recommends that analgesics be prescribed starting at Step 1 (nonopioid analgesics, such as acetaminophen or nonsteroidal anti-inflammatory drugs [NSAIDs] with or without adjuvant therapy). If the pain persists or worsens, the clinician prescribes pain relievers from Step 2, described as “weak opioids,” with or without a nonopioid and with or without adjuvant therapy. At this point, if pain persists or worsens, the patient is administered a “strong opioid,” with or without a nonopioid and with or without adjuvant therapy (Step 3). Thus, pain therapy is based on pain intensity and patients progress through the steps one by one, from lowest to highest, until pain relief is obtained. The terms “weak” and “strong” opioid are rarely used today. The WHO pain ladder lists codeine, hydrocodone, and tramadol as “weak opioids,” and morphine, oxycodone, methadone, hydromorphone, and fentanyl as “strong opioids.”4

Pain treatment failure occurs when the third step of the treatment ladder is not enough to adequately control pain. For the purposes of this paper and the patients described here, I provide a more detailed description of the WHO third step: “A prior and/or current regimen of nonpharmacologic measures such as physical therapy, electromagnetic, or psychotherapy and multiple pharmacologic therapies that may include anti-inflammatories, antidepressants, neuropathic (antiseizure) therapies, topical analgesics, corticosteroid injections, and a daily opioid dosage of 100 mg or more of morphine equivalents.”3 

Recognition of Failing Patient

The physical, emotional, and economic impact of poorly controlled pain is well documented.5-12 Patients with inadequately managed centralized (neuropathic) pain often exhibit a common behavior pattern (Table 1). They complain of inadequate pain relief and demand more medication. This sometimes causes the pain practitioner and his or her staff to label such patients as “drug seekers,” “addicts,” or “difficult.”1 In reality, these patients might actually need more medication (or a change in medications). Patients with chronic pain who are not receiving adequate pain control often will present ahead of their scheduled appointments, frequent emergency rooms, and see more than one physician.2 These patients often lose their jobs, social contacts, and former way of life.5-12 They usually become reclusive and are housebound or bedbound. Proper hygiene, nutrition, and social contacts diminish, and patients and their families might develop hostile, angry demeanors, often directed at the pain practitioner.1 Severe uncontrolled pain can seriously impair attention span and memory, so patients might miss appointments or other instructions, causing them to be labeled as “non-compliant.” Rather than pejoratively labeling these patients, practitioners should consider them treatment failures and evaluate them accordingly.

New Diagnostic Developments

Several scientific developments recently have occurred that make it possible to objectively evaluate the chronic pain patient who is failing standard treatment. The first is the understanding of pain centralization.13-16 Referred to by various names, including neuropathic pain, central pain syndrome, central sensitization, or chronic pain syndrome, the basic pathology is the same—microglial cell activation, neuroinflammation, cellular destruction, and implantation of pain sensation in the cells of the central nervous system (CNS).13-16 Centralization of pain can occur from:

  • direct injury to the brain, such as trauma, infection, or stroke,
  • disease processes, such as fibromyalgia, multiple sclerosis, migraine, etc.
  • peripheral nerve injury or disease that activates both a CNS and peripheral disease process.13

Regardless of the initial cause of the injury (pain event), microglial cells in the spinal cord and brain become activated, resulting in neuroinflammation, metabolic disturbances, and tissue destruction by phagocytosis.12-14 Typical clinical manifestations are constant pain, insomnia, fatigue, depression, mental impairment, allodynia, hyperalgesia, and excess sympathetic discharge.13,15 These manifestations make it possible to clinically determine if centralization has occurred, as has been seen through recent magnetic resonance imaging (MRI) imaging of the brain.15

In addition to recent knowledge concerning pain centralization, considerable information has emerged about aberrant opioid metabolism, including gastrointestinal malabsorption, cytochrome P (CYP) 450 deficiencies, and receptor sensitivities. Laboratory testing is available for several genetic defects, hormone abnormalities, and biomarkers of neuroinflammation. Quantitative blood and urine tests make it possible to identify patients with metabolic abnormalities, such as gastrointestinal malabsorption and CYP450 aberrancy. Prior to the advent of these laboratory tests, treatment of the chronic pain patient solely was based on the patient’s symptomatology, including the typical pain score of 1 to 10. This total reliance on symptoms often led to unnecessarily high opioid dosages. All the diagnostic tests described in this report are available throughout the United States and can be used by any practitioner to evaluate the chronic pain patient who is failing standard treatment.

Diagnostic Evaluation Protocol

The author evaluates patients who present to him as failing standard treatment with a routine diagnostic protocol. First, there is an initial assessment to determine if the patient’s pain is centralized.13 Second, a careful history is taken to determine if opioid malabsorption is present and could be the underlying cause of treatment failure.17 Critical to the history is whether oral opioids provide much relief and if the patient has had multiple abdominal, pelvic, or spine surgeries that may cause adhesions or impairment of nerve innervation to the intestine. Also, does the patient have diabetes or an autoimmune disorder know to affect the intestine. Third, blood is drawn, urine samples are taken, and laboratory profiles of several genetic markers, serum hormone levels, and neuroinflammatory biomarkers are ordered.

The major purpose of the protocol primarily is to determine if there is a cause(s) of treatment failure, such as opioid malabsorption, genetic metabolic defect, or severe hormone insufficiency that can be easily and rapidly corrected. Neuroinflammatory markers are studied to determine if they are elevated. If elevated, the patient may benefit from neuro-antiinflammatory treatment, including modulators of overactive microglial cells. Low quantitative urine or blood levels of opioids can help confirm the presence of a genetic metabolic defect or gastrointestinal malabsorption. By using this diagnostic protocol, it has become quite clear to the author that there are multiple reasons for treatment failure that can be determined and a treatment strategy can be developed based on underlying genetic and physiologic abnormalities.


Clinical Settings and Case Presentations

The diagnostic evaluation and treatment setting for the cases reported here is the Veract Intractable Pain Clinic, in West Covina, California. The clinic was established in 1975 within the Los Angeles County public health system to treat patients with severe pain who were failing opioid therapy, including high-dose opioids. The original mission of the clinic essentially has remained to this day. Patients are referred by their physician(s) because they have failed standard medical treatments, including high opioid dosages. Most patients at the time of referral are bedridden or house bound.

Patients must attend the clinic with their family, and special consent and opioid agreements, as well as structured, regular attendance are required. Patients and their family must affirm that the patient has not had a history of abuse, must agree to comply with program rules, and must keep the prescribed medication in a safe place. The goals of treatment are to end the patients’ reclusive, nonfunctional state, and to help them develop functional social and physical skills that enable them to perform normal activities of daily living and to achieve a better quality of life. The clinic does not treat patients who are victims of abuse, patients with a history of addiction, patients with a history of intravenous drug use, and patients who are actively using illegal drugs, including cocaine, methamphetamine, marijuana, and heroin. Patients with pending worker’s compensation or other litigation also are excluded.

Patients who are failing standard treatment are allowed to remain on any pharmacologic or non-pharmacologic measure they believe provides some pain relief. New or modified treatments based on the patient’s diagnostic evaluation, pain symptoms, and family observations are added or changed at regular monthly visits until the above-stated treatment goals are reached.


Case Series

Between January 1, 2012 and December 31, 2014, 101 patients were referred for evaluation and clinical management because they were failing standard pain treatment. There were 39 men (38.6%) and 62 women (61.4%); ages ranged from 29 to 74 years. All had failed standard treatment (Step 3 of the WHO ladder). All patients had attempted a wide variety of antidepressants, neuropathic agents, and anti-inflammatory agents. At the time of referral, all were taking an estimated daily opioid dosage of 100 mg or more of morphine equivalent. The major underlying causes of their pain are listed in Table 2.

All the patients were determined to have centralized pain through patient assessment.13 They all stated their pain was constant and interfered with sleep, physical functions, and activities of daily living. All reported episodes of hyperalgesia or allodynia and demonstrated 2 or more of the following physical sign of excess sympathetic discharge: hypertension, tachycardia, hyperhidrosis, mydriasis, hyperreflexia, hyperthermia, and vasoconstriction (cold hands or feet). Patients had been receiving opioid treatment before referral for 2 or more years and had their painful condition for a minimum of 5 years. At the time of referral, all patients were taking 1 to 4 oral opioids and at least 4 ancillary or adjunctive medications.

Patients were evaluated using the diagnostic protocol described above. The hormone and neuroinflammatory profiles did not start to become available until 2013, so all 101 patients were not tested for those parameters. Results of the diagnostic laboratory profiles are reported below.


Opioid Malabsorption

Every patient who reported little or no pain relief with oral opioid administration or had a low serum or urine opioid level was evaluated for the presence of opioid malabsorption.17 A detailed history was taken to determine if the patient had a disease or surgical procedure that may have disturbed bowel motility or function (Table 3). These included abdominal and/or pelvic surgeries, such as bariatric surgery, and surgeries or trauma that may have affected the vagus or splanic nerves within the autonomic nervous system. Since CYP450 enzymes are ubiquitous in the intestine and have opioid transport as a physiologic function, the presence of multiple defective CYP450 enzymes was considered as a possible contributor to malabsorption. The major confirmatory procedure was a low dose (1-3 mg) injection of hydromorphone to determine if a non-oral route of administration produced the physiologic opioid effects of pain relief, pupil constriction, and pulse rate reduction. Twenty of the 101 (19.8%) patients in this series demonstrated opioid malabsorption and subsequently were successfully managed by opioids given by non-oral routes of administration.


Genetic Testing

All patients had CYP450 enzyme testing by buccal swab for CYP450 2D6, 2C9, and 2C19 (Genelex, Seattle). Normal CYP450 activity was termed “extensive.” Other levels of enzyme activity were termed poor, rapid, or intermediate and were considered abnormal or defective. Ninety-one patients (90.1%) had 1 or more CYP450 abnormalities or defects; 28 patients (27.7%) had 2 defects, and 8 patients (7.9%) had 3 defects or abnormalities (Table 4). In recent months, a number of other CYP450 enzyme tests, such as 3A4 and 3A5, have become commercially available. Also, some genetic pharmacodynamics tests including opioid mu receptor 1 and catechol-o-methyltransferase show early promise for determining the need for high-dose opioid therapy and the cause of treatment failure. Recently, these new genetic tests have been added to the author’s diagnostic protocol, but meaningful data are not yet available.

Inflammatory and Metabolic Biomarkers

Numerous animal and in vitro studies point to neuroinflammation as the underlying factor in centralized pain.14-18 Biomarker profiles for neuroinflammation and CNS metabolic defects recently have become available to pain practitioners. In 2013 and 2014, 80 failing patients were tested with a diagnostic profile consisting of 9 biomarkers, plus an erythrocyte sedimentation rate and C-reactive protein (Table 5) (Ridge Diagnostics, Research Triangle Park, North Carolina). Although a serum assay for an inflammatory marker cannot precisely determine if the marker is from a peripheral or central source, the biomarkers tested here undoubtedly represent at least some neuroinflammation. Results in these patients support the finding of neuroinflammation in animal studies.16 Also, biomarkers of neuroinflammation have been found in the spinal fluid of humans.17 Recently, using a special MRI technique, investigators were able to identify neuroinflammation in the brains of chronic pain patients.15 In summary, neuroinflammation is quite common, if not universal, in pain patients who fail standard treatment. At this early juncture, it cannot be positively stated, but specific treatment directed at neuroinflammation and microglial overactivation might be necessary to adequately treat some patients who are failing standard treatment.


Hormone Profiles

Although hormone testing is hardly new, it is relatively recent that pain practitioners can rapidly and conveniently access profiles consisting of multiple hormones. The recent discovery that the CNS makes and uses some hormones for neuroprotection and neurogenesis compels hormone testing of pain patients because these 2 physiologic mechanisms are critical for pain management.19,20 Also, it now clearly is known that analgesics, particularly opioids, are not effective if some hormones, such as cortisol, pregnenolone, and testosterone, are deficient.19 Some hormones, such as adrenocorticotropin and cortisol, serve as biomarkers of uncontrolled pain and signal that increased analgesia may be necessary.21,22 The hormone protocol used by the author consists of 3 hormones made in the CNS and the periphery: 1) pregnenolone, 2) progesterone, and 3) dehydroepiandrosterone. Additionally adrenocorticotropic hormone (ACTH), cortisol, and testosterone are tested. Testing of 61 patients with this 6-hormone profile in 2013 and 2014 showed 1 or more hormone abnormalities in 49 of 61 (80.3%) patients (Table 6). Significant pituitary-adrenal-gonadal insufficiency, defined as a low ACTH plus 2 other adrenal/gonadal deficiencies, was found in 7 (11.5%) patients. Severe cortisol deficiencies (levels <1 mcg/dL) were found in 3 patients (4.9%), and testosterone levels were only at trace levels (<3.0 ng/dL) in 6 patients (9.8%). Although severe, chronic pain likely is the biggest contributor to these abnormalities, other factors such as opioid suppression, psychological stress, and inadequate nutrition might play a role.19,23 Regardless, the hormone deficiencies that were identified in these studies appeared to be a contributing factor to the failure of standard pain treatment in some patients, and as the hormone levels normalized, the patient’s reached their treatment goal.



Today, a major unmet need in pain management is patients who are failing to find relief with standard treatment. These often are desperate patients who seek multiple sources of care only to be disappointed. Until now, these patients could only be treated according to their complaints of uncontrolled pain, which often led to the prescription of higher opioid dosages. In reality, these patients may have a genetic or other physiologic reason(s) for treatment failure and might need to be evaluated with a diagnostic protocol such as the one described here. This protocol assesses genetic abnormalities, opioid malabsorption, hormone deficiencies, and neuroinflammation (Table 7). The author recognizes that the proposed diagnostic protocol can be expensive, extensive, and time-consuming for both patients and their physicians.

In the author’s experience, all the patients reported about here appeared to have centralized pain. Diagnostic studies showed a very high prevalence of genetic metabolic defects, opioid malabsorption, high serum neuroinflammatory markers, and hormone abnormalities. These patients need to be viewed as extremely ill, physiologically and psychologically dysfunctional, and in need of a diagnostic evaluation and a specific, tailored treatment strategy. Although the information and findings reported here are preliminary and will undoubtedly be refined in the future, pain practitioners need to acknowledge that there is a significant subgroup of chronic pain patients who are failing standard treatment and need a diagnostic evaluation and treatment strategy tailored to diagnostic findings.

Last updated on: June 16, 2015
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Chronic Pain Patients Who Fail Standard Treatment: Now What?

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