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11 Articles in Volume 13, Issue #6
Ask the Expert: Cash Patient on High-Dose Oxycodone With Negative Urine Screens
Cluster Headache: Providing Relief for a Debilitating Disorder
Editor's Memo: Keeping the Trust in Difficult Times
Gout: New Guidelines for Managing An Ancient Disease
History of Pain: A Brief Overview of the 17th and 18th Centuries
Letters to The Editor: Guidelines for Opioid Prescribing, Drug Legislation
Long-term Opioids, Sickle Cell Disease, and Pain Patches
Lumbar Spinal Stenosis: A Review of the Treatment Options and Modalities
Malabsorption of Opioid Medications
Non-Opioid Pharmaceutical Treatment of Cancer Pain
Treatment of Postherpetic Neuralgia With Low Level Laser Therapy

Malabsorption of Opioid Medications

The prevalence of opioid malabsorption is unknown, but it appears to be common enough that it should be considered by pain practitioners, and may be one of the reasons why an intractable pain patient may not respond well to oral opioids.

Not all patients respond the same to any given opioid. This fact is well known to pain practitioners. In this journal, we have previously discussed some of the reasons why this occurs—genetic polymorphism, pharmacokinetics, and pharmacodynamics. But one less obvious reason may be opioid malabsorption.

The prevalence of opioid malabsorption is unknown, but it appears to be common enough that it should be considered by pain practitioners, and may be one of the reasons why an intractable pain patient may not respond well to oral opioids. In this paper, I will outline the clinical characteristics of this condition, and describe two techniques I use to determine whether malabsorption in present.

One of these tests is what I call an “opioid tolerance test,” which requires low-dose subcutaneous injections of morphine or hydromorphone over a 2-hour period. The other technique is a dual blood test to determine opioid blood level before and after an observed dose of oral opioids. The dual blood test involves assessing the blood level before and 1 hour after dosing, and is done at the same office visit. If you suspect malabsorption, you should refer to a pain specialist. I do not recommend primary care physicians conduct these tests in their offices.

In addition, I present a series of 10 cases of patients who have been identified as malabsorbers and possible alternative delivery routes.

What Causes Opioid Malabsorption?

The primary cause of malabsorption of opioids appears to be genetic. Normally, most oral opioids are absorbed into the serum through the small intestine, and travel to the liver where they are metabolized by the cytochrome, or alternate metabolic pathway usually called “glucuronidation.” Genetic polymorphisms in metabolizing enzymes and transporters of opioids have been linked to variability in opioid response.1-3 The intestine is filled with opioid receptors and cytochrome P450 (CYP450) enzymes. Next to the liver, the intestine has the highest concentration of cytochrome enzymes.4-6 The role of opioid receptors in the intestine is incompletely understood. Receptors probably have some role in transport of opioids across the intestinal wall. If so, genetic abnormalities of receptors will interfere with absorption (Table 1).1,2

My clinical experience indicates that CYP450 defects may cause malabsorption. Cytochrome P450 enzymes are known to start metabolism of some opioids before the opioid crosses the intestinal wall into the serum.7-10 Without adequate CYP450 function, opioids may not metabolize in the intestine and fail to cross the intestinal wall into the serum. All of the patients I have observed with opioid malabsorption have one or more CYP450 abnormalities, although this finding may not be the sole cause for their opioid malabsorption, because these patients may also have an autoimmune disorder, diabetes, or have had gastrointestinal (GI) surgery.

In addition to genetic defects, three medical conditions can lead to opioid malabsorption in pain patients: type 2 diabetes mellitus; GI surgery, including weight control procedures; and autoimmune disorders.

Diabetes is known to cause pathologic changes in the GI tract and produce malabsorption.11-13 Gastroparesis is the best known complication, but malabsorption occurs in some patients with diabetes.11 GI surgery, such as gastric bypass for weight control, is now commonplace and may cause malabsorption of opioids. GI banding or removal of portions of the stomach or intestine to control weight may disturb normal transit and/or alterations of bacterial flora, which lead to malabsorption.14 Autoimmune disorders may attack the stomach and intestine.15,16 Crohn’s disease, ulcerative colitis, and celiac disease are recognized autoimmune diseases known to cause malabsorption, but the stomach and intestine may be attacked by any number of other autoimmune disorders.15,16 In some cases (ie, Crohn’s disease or ulcerative colitis), damaged intestine is surgically removed and may cause malabsorption and too rapid transit.14

Suspicion of Opioid Malabsorption

A suspect of opioid malabsorption is simply a person who reports that multiple oral opioids have not been effective in relieving their pain. Take a brief history of that patient. Did they report good pain relief when they were given an injection or suppository formulation of an opioid in a hospital or emergency room? Did they report good pain relief after sublingual or transdermal administration of an opioid? Have they observed whole opioid tablets in their feces?

Physical examination of these patients may demonstrate inadequate pain control as demonstrated by hypertension, tachycardia, mydriasis, allodynia (pain to light touch), or hyperalgesia (excess pain on pressure). Laboratory testing may show low or zero serum opioid concentrations and abnormal serum hormone levels typical of chronic, severe, uncontrolled pain (eg, cortisol, pregnenolone, or adrenocorticotropin). In my experience, any patient with a CYP450 defect, particularly when accompanied by an autoimmune disorder, may be a potential malabsorber.

Case Series

Ten adult women who were referred to my practice over the past 2 years were suspected of having opioid malabsorption (Table 2). All 10 patients have required non-oral routes of opioid administration to achieve pain control. All 10 attempted multiple oral opioids without success. All showed one or more CYP450 abnormalities and various hormone deficiencies. Six of the 10 (60%) have an autoimmune disorder determined by the presence of multisystem disease and the presence of various inflammatory and protein markers. All patients were determined to have malabsorption by the opioid tolerance test described below.

Since diagnosed with malabsorption, all 10 patients have had significant and even dramatic pain relief when they were administered opioids by non-oral routes. Nine of the 10 (90%) require subcutaneous injections of hydromorphone and the tenth patient received subcutaneous morphine to control their pain. Other opioids employed by the patients included transdermal fentanyl and/or sublingual oxycodone or morphine. In one case each, oral methadone or oxymorphone was somewhat effective. Those patients who had to take injectable morphine or hydromorphone at home attended, with a family member, a special class to learn how to safely give themselves opioid injections. Included in the training was the use of emergency naloxone and safe storage of supplies. It is emphasized that these were rare patients, and this means of opioid administration should only be done as a last resort measure in patients who are very responsible, disciplined, and have good intelligence.

My Malabsorption Test

As noted, there are two ways I document malabsorption of opioids (Table 3, page 34). In the first test, I take an opioid blood level before and 1 to 2 hours after an observed oral opioid dose is taken. In the second, I perform an opioid tolerance test using injectable hydromorphone or morphine. Similar to the opioid blood level test, prior to the opioid tolerance test the patient should orally ingest 1 of these 2 opioids by the oral route and demonstrate that no pain relief or physiologic effects such as pupil constriction, decreased pulse rate, lowered blood pressure, or reduced reflexes will occur. This information can be ascertained prior to or on the same day as the test procedure. The concentration of morphine or hydromorphone I use for this procedure is 30 to 50 mg/mL, so small subcutaneous dosages can be administered.

Dosages of 1 to 5 mg are given subcutaneously every 15 minutes up to 2 hours. Once the injectable dose of morphine or hydromorphone produces pupillary constriction and pain relief, no additional dosages are given. The ongoing treatment dosage is about one-half to one-third the total dosage that produces the opioid physiologic effects of pupil constriction, reduced pulse and blood pressure, and pain relief. It is critical to have naloxone available in the rare event of over-sedation. Patients with opioid malabsorption will usually demonstrate pupillary constriction and pain relief with a low injectable opioid dosage.

The advantage of an opioid tolerance test is that a treatment dosage can be determined at the time of the test so that the patient can proceed with immediate and ongoing pain relief. If a diagnosis of malabsorption is made only by blood level determination, an alternative route of administration (patch, buccal film, nasal spray, or in-office injection) and effective dosage will have to be determined.

Alternative Routes

Once malabsorption is established, it is important to switch to an opioid that can be administered by non-oral routes, such as sublingual, suppository, transdermal, intrathecal, or injection (Table 4). Transdermal buprenorphine (Butrans) or fentanyl may be good choices. Sublingual opioids are ideal. When alternatives to the oral route are selected, many factors enter into the clinical selection. Included here are cost, tolerance to skin patches, genetic variance (CYP450 defects), and availability of a compound pharmacist to make sublingual and injectable preparations. I have found that morphine, oxycodone, hydromorphone, and methadone all work by the sublingual route in selected patients. Also, it may be necessary to try more than one measure before settling on one. Some patients may at least partially absorb one or more opioids. While injectable opioids are not desirable, they likely will have to be used in some malabsorption cases. My choice is predominantly hydromorphone because it is not metabolized by the CYP450 system.

Apparently, malabsorption has always been with us. The Merck Manual of 1956 states, “Mild pain usually responds to the oral use of salicylates or salicylate combined with acetophenetidin. More severe pain requires the oral or subcutaneous use of codeine, meperidine, methadone, dihydromorphinone, metapon, or morphine.”17 In the event that an opioid patient has not attempted anti-inflammatory and neuropathic agents, they can be added to a regimen, although these agents may also be poorly absorbed by the oral route.


Oral opioid malabsorption should be suspected when a pain patient reports that multiple oral opioids have been ineffective. Most malabsorption patients observed by the author have CYP450 defects. Cytochrome P450 defects appear to impair opioid GI absorption since opioid metabolism actually begins inside the intestine.4-10

I document malabsorption by taking an opioid blood level before and after an observed oral opioid dosage or by the use of an opioid tolerance test, which entails small injectable dosages of morphine or hydromorphone over a 2-hour period. Once malabsorption is recognized, non-oral routes of opioid administration will have to be utilized. Choosing the appropriate alternative route will require careful consideration of the patient’s underlying pain condition, disability, co-morbid conditions, and whether they are living alone, with a caregiver, or in an assisted-living situation.

Last updated on: October 26, 2015
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