Thursday, 6 December 2018

Little Hope In The Future For Nerve Pain Patients Who Don't Respond To Standard Treatment

Today's extensive post from (see link below) takes an in-depth look at patients with chronic pain conditions, who don't respond to standard pain treatments. Now if ever there was a disease that falls under this category, it's neuropathy. Neuropathy is treated generally with medications that are actually designed for other diseases altogether and that has been the case for decades as scientists struggle to find effective treatments for nerve pain. It's little wonder then that there's a high failure rate for these drugs. This article looks at how and why this happens and as such is useful information for chronic neuropathy patients who consistently fail to achieve pain reduction under their current therapy. The article concentrates on the evaluation and diagnosis of this sort of patient and presents an evaluation process that rarely takes place in such depth in the real world, unless you have a highly conscientious doctor/neurologist who is prepared to put in the time and effort. It's complex and time consuming for both doctor and patient although you would hope that all patients would receive such careful attention. The fact that they don't means that standard treatments will continue, with all their failures, frustrations and disappointments. However, given the time and cost pressures on all doctors at the moment, there's little chance that this will change in the near future - it's a vicious circle. Add to that the fact that most patients are just in search of symptom relief and don't want to spend months as a research subject and drugs like Lyrica and Gabapentin (and others) will continue to form a risk for nerve pain patients across the world.

Chronic Pain Patients Who Fail Standard Treatment
By Forest Tennant, MD, DrPH
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.

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 3="" 6="" a="" abnormalities="" although="" and="" as="" at="" biggest="" chronic="" contributor="" dl="" factors="" found="" in="" inadequate="" is="" levels="" likely="" mcg="" might="" ng="" nutrition="" only="" opioid="" other="" pain="" patients="" play="" psychological="" role.="" severe="" stress="" such="" sup="" suppression="" testosterone="" the="" these="" to="" trace="" were="">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.

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