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11 Articles in Volume 7, Issue #9
CES in the Treatment of Addictions: A Review and Meta-Analysis
Chronic Cancer Pain Management
Compliant Billing, Coding and Documentation for Interventional Pain Management
Critical Transition from Short-to-Long-Acting Opioid Therapy
Dextrose Prolotherapy and Pain of Chronic TMJ Dysfunction
Dysfunction and Rehabilitation of the Shoulder
Low Level Laser Therapy (LLLT) - Part 2
Placebos in Pain Management
The Good Patient: Responsibilities and Obligations of the Patient-physician Relationship
TMJ Derangement and SUNCT Syndrome Co-morbidity
Ziconotide Combination Intrathecal Therapy

Critical Transition from Short-to-Long-Acting Opioid Therapy

While most pain patients are initially treated with short-acting opioids, severe unremitting pain involving biological manifestations requires transitioning to long-acting opioids—but not on the basis of equivalency tables. Instead, long-acting opioids should be carefully phased in at low dosages while keeping the short-acting opioid regimen in place until it can be safely curtailed.

Hydrocodone-acetaminophen compounds (HCA) and other short-acting opioids are now among the most commonly prescribed drugs.1,2 This is indeed a tribute to physicians who have elevated treatment of pain problems in their practices to a position of prime importance—as it should be. In their current formulations, HCA compounds and other short-acting opioids have proved to be extremely versatile and effective. They are relatively safe and effective for practically any painful condition including musculo-skeletal maladies, headaches, and rheumatologic disorders.

Unfortunately, HCA and other commonly prescribed short-acting opioids—including codeine, meperidine, hydromorphone, and oxycodone-acetaminophen compounds—may not adequately control severe, chronic pain by themselves. The failure to control severe, chronic pain with short-acting opioids invariably occurs in a patient who complains of severe, constant, or persistent pain. Although the number of chronic pain patients in this category is not known precisely, they are grossly under-treated at this time. These patients experience flares or exacerbations that may last for a few hours or several days. Often the flare is referred to as breakthrough or rescue pain (see Table 1). Despite HCA or other short-acting opioid treatment, a long-acting opioid is indicated. A common tip-off to today’s practitioner is the patient who reports that six to eight separate dosages of HCA or other short-acting opioids a day aren’t enough to control pain. In addition, practitioners commonly encounter patients who exceed the safe daily acetaminophen dose of about 3500 to 4000mg a day.

Although the physician may recognize the clinical necessity of a long-acting opioid, the morbidity and mortality associated with initiation of long-acting opioids has proved a medical hazard. The nation has recently experienced an epidemic of deaths associated with the use of the long-acting opioids oxycodone and metha-done. I have recently reviewed numerous cases of death where a physician attempted to transfer a patient from HCA or other short-acting opioids to long-acting opioids (see Table 2).

These deaths have resulted in numerous malpractice and product liability lawsuits. In these cases, the physician almost always attempted to totally substitute a long-acting opioid for a short-acting opioid. Often the physician attempted to follow one of the typical published opioid conversion tables.

Immediate and total substitution of a long-acting opioid for HCA or other short-acting opioid is hazardous and should rarely be done. This article describes my method of initiation of a long-acting opioid in patients who are currently using a short-acting opioid with ancillary medication such as benzodiazepines, muscle relaxants, and anti-depressants. I estimate having used this procedure on over 1,000 chronic pain patients over a 30-year period, and have never experienced a death in my practice.

Simple Method to Initiate Long-Acting Opioids

My method to initiate long-acting opioid therapy is simple (see Table 3#). Rather than stop HCA, meperidine, or other short-acting opioid, merely continue the short-acting and add a low dose of long-acting opioid to the regimen. Leave the patient on this low dose for 72 or more hours to insure that there is no drug interaction, over-sedation, drug sensitivity, or allergic reaction. If there is no adverse event in this 72 hour period, titrate the dosage of long-acting opioid upward to increase pain control over the next six to twelve weeks. Allow the patient to continue HCA or other short-acting opioids on an as-needed basis for breakthrough pain or flares. The patient is instructed to only reduce or stop their short-acting opioids and ancillary medications on a schedule that provides them maximal pain relief.

By this method, severe chronic pain patients will, over a period of six to twelve weeks, settle on a quite stable regimen of a combination of long and short-acting opioids and ancillary medications. Patients treated by this method achieve significantly better pain control and enhance their physical, mental, social, and vocational status. I have now followed 20 of these patients for over 20 years.

Physiologic Basis For Methodology

There are two basic types of chronic pain: intermittent and constant. Intermittent pain is the most common form of chronic pain and encompasses headaches and musculo-skeletal disorders. The constant form is permanent and is characterized by existing biological manifestation (e.g. neurologic defect) that produces constant pain. While some flares or breakthrough episodes appear to be precipitated by such events as intentional movement, stress, or concomitant illness, others have no discernable etiology. To control constant pain caused by permanent neurologic defect, a critical blood level of opioid must be maintained at all times including sleep-time. A physician who attempts to control constant, baseline pain with short-acting opioids may witness their patient escalating their dosage—often to unsafe levels. In addition, patients may attempt to use ancillary medications including benzodiazepines, muscle relaxants, anti-inflammatory agents, anti-depressants, and even alcohol or illegal drugs in an effort to control their pain. The clinical picture may falsely appear as if the patient is randomly abusing medication when, in reality, the patient needs a long-acting opioid to suppress the baseline pain. Once baseline pain is adequately-controlled, one can then reduce the use of short-acting opioids and ancillary medications. Patients who compulsively seek relief in the face of poorly-controlled pain are referred to as pseudoaddicts.

“Due to this safety fact, long-acting opioids, in the opinion of this author, should never be prescribed to opioid naive patients until short-acting opioids prove inadequate.”

The Methadone Maintenance Model

My method of initiating a long-acting opioid is patterned after the model used in methadone maintenance clinics which treat heroin addicts. In these clinics, the starting methadone dose is 20 to 40mg a day. Over 60 to 90 days the daily dosage is progressively raised to a maximum of about 100-180mg a day.

Why is the first day dose so low? Simple. The heroin addict is known to concomitantly use benzodiazepines, alcohol, marijuana, and multitudes of other drugs. Additionally, his tolerance is incompletely known and subject to a variety of factors such as daily opioid dose, longevity of use, gastrointestinal absorption, and liver disease. The first methadone dose is given orally in front of a nurse or physician, and the patient must wait 30 minutes to be sure an anaphylactic or other adverse reaction doesn’t occur. Over 100,000 heroin addicts are treated each day in methadone maintenance clinics across the country. These clinics have been in existence since 1965. Their safety record has been remarkable considering that heroin addicts are far less compliance-prone than the average pain patient. In these clinics, the method of beginning the long-acting opioid, methadone, at a low dose and titrating upward over a few weeks has resulted in almost negligible overdose deaths in the first month of treatment.

Dangers of Long-Acting Opioids

There is some misconception that long-acting opioids are safer than short-acting ones. This false belief is clearly contraindicated by the fact that all long-acting opioids are in Schedule II of the Controlled Substance Schedule, while most short-acting opioids—including HCA—are in Schedule III. The hazards of long-acting opioids derive principally from the fact that they will maintain a blood level for many hours white short-acting opioids don’t maintain significant blood levels for more than 2 to 4 hours. The major, acute danger with a long-acting opioid is a drug interaction with another drug, because any drug taken during a high opioid blood level period is a potential hazard. Due to this safety fact, long-acting opioids, in the opinion of this author, should never be prescribed to opioid naive patients until short-acting opioids prove inadequate.

Table 1. Terms Commonly Used for the Two Components of Chronic Pain
Component 1 Component 2
Baseline Flares
Persistent Breakthrough
Intractable Rescue
Constant Incident
Table 2. Commonly Used Long- and Short-Acting Opioids
Long-Acting
Fentanyl Transdermal (Duragesic®)
Methadone (Dolophine®)
Morphine (Avinza®, Kadian®, Oramorph®)
Oxycodone (Oxycontin®)
Oxymorphone (Opana Er®)
Short-Acting
Codeine
Fentanyl (Actiq®, Fentora®)
Hydrocodone (Vicodin®, Norco®, Lortab®, Vicoprofen®)
Meperidine (Demerol®)
Morphine
Oxycodone (Percocet®, Percodan®, Endocet®)
Oxymorphone (Opana®)
Propoxyphene (Darvon®, Darvocet®, Darvon-N®)

Long-acting opioids may have an adverse interaction with a wide variety of compounds including benzodiazepines, muscle relaxants, alcohol, sedatives, anti-depressants, and anti-seizure agents. Consequently, a toxic interaction may occur which results in respiratory suppression, allergic reaction, or cardiac arrhythmia. Epidemiologic reviews show that a great majority of these interactions occur within the first day or two after starting long-acting therapy. Due to this potential danger, long-acting opioids must be initiated at a low dose during the first 72 hours to minimize risk. At a low dose, liver and renal clearance of the long-acting opioid will usually protect against a catastrophic adverse, potentially fatal, reaction.

The decision to initiate long-acting opioid therapy must be taken very seriously, since the constant high blood levels of opioids may suppress hormone production in multiple glands and result in many hormonal complications.3 Long-acting opioid therapy requires regular clinic monitoring, hormone replacement, weight reduction, and periodic opioid change (“rotation”). Only physicians with a structured practice and who are prepared to provide these clinical treatments should attempt long-acting opioid therapy. Patients need to be thoroughly educated on the benefits, hazards, and procedures used to initiate and maintain long-acting opioid therapy (see Table 4).

Table 3. Simple Method To Initiate Long-Acting Opioid Therapy
  1. Leave patient on current short-acting opioid and ancillary drug regimen.
  2. Start a low dose of long-acting opioid. (See Table 6.)
  3. Leave patient at the low dose of long-acting opioid for at least 72-hours.
  4. Titrate the long-acting opioid dosage upward over several days or weeks until there is good pain control without sedation or impairment.
  5. Let patient drop out or reduce their short-acting opioids and ancillary drugs as they feel comfortable in doing so. Leave the patient on their short-acting opioids for flares or breakthrough pain.
Table 4. Patient Education On Initiation Of A Long-Acting Opioids
  • Short-acting opioids are not effective, by themselves, for severe persistent or baseline pain. A long-acting opioid is required.
  • Short-acting opioids are to be continued for breakthrough or flare pain.
  • The initial dosage of long-acting opioid is low and may not provide additional relief for several days or even weeks.
  • Long acting opioids are primarily for “pain prevention” which suppresses the baseline pain and may lower the intensity of flares, but won’t eliminate them.
  • The patient must not attempt to supplement their long-acting opioid or potentiate it with benzodiazepines, muscle relaxants, alcohol, or other sedatives until a maintenance dose is achieved.
  • Short-acting opioids and ancillary medications may be reduced or even eliminated after stabilization with a long-acting opioid.
Table 5. Indications For Long-Acting Opioids
  • Failure to control pain with 8 or more dosages of hydrocodone or other short-acting opioid a day.
  • Family member or health professional states that the current opioid regimen is ineffective.
  • Frequent visits to emergency rooms or multiple doctors to find relief (“Pseudoaddiction”)
  • Presence of biologic symptoms: Anorexia, Hypertension, Insomnia, Tachycardia, Memory Loss, Bed/House Bound, Immobility, Depression

Indications for a Long-Acting Opioid

The most easily recognized indication in medical practice is likely the patient who is taking over 8 dosages of HCA a day and/or exceeding the maximal recommended daily dosage of acetaminophen (about 3500 to 4000mg per day; see Table 5). These patients may demonstrate pseudoaddiction in that they visit multiple physicians or emergency rooms in a vain attempt to find adequate relief that can only be provided by a long-acting opioid. Family members or a medical person such as a nurse or pharmacist may call a physician’s office and simply leave a message that the current pain treatment regimen is inadequate. Physicians should be aware that this tip-off is an indication that a long-acting opioid may be necessary. Staff should be trained to listen, receive, and report the necessity for more pain relief. More than one physician has gotten well-acquainted with lawyers for failure to heed this signal for help.

Table 6. Initial and First 72 Hour Dosages of Long-Acting Opioids
Opioid Initial Dosage+
Fentanyl Transdermal 50 to 75mcg every third day
Methadone 5 to 10mg every 4 to 6 hours
Morphine (24 hour formulation) 30mg every 24 hours
Morphine (12 hour formulation) 20mg every 12 hours
Oxycodone 10 to 20mg every 12 hours
Oxymorphone 5 to 10mg every 12 hours
+These dosages assume the patient is opioid tolerant since the patient is already taking short-acting opioids.

A more specific way to identify patients in need of a long-acting opioid is to search for evidence that pain is adversely affecting some of the body’s normal biologic functions. Invariably these patients will have persistent or a baseline pain. Upon inquiry, the patient will state that their pain is constantly present except during sleep. Patients relate that they have diminished appetite, sleep, mental concentration, and libido. They stop social contacts and are often bed- or house-bound. Particularly, during pain flares or episodes of breakthrough pain, they demonstrate pulse rates about 84 per minute and oftentimes over 120 per minute. Blood pressure may be continuously or episodically elevated. If tested, the patient will almost always demonstrate hormone abnormalities of the pituitary, adrenal, or thyroid glands.3 The presence of multiple biologic abnormalities (e.g. “biologic pain syndrome”) is a strong indication for a long-acting opioid.

Selection of Long-Acting Opioid

The selection of a long-acting opioid by the practitioner is invariably influenced by the patient’s health plan and/or financial ability to pay. There is emerging evidence that patients may be truly allergic to either a specific opioid and/or a component of the tablet, capsule, or patch formula.4 Inquiries should be made as to the allergic potential in each patient prior to initiation of long-acting opioid therapy. Due to the vagaries of health plan formularies and allergic/sensitivity reactions, practitioners who prescribe long-acting opioids should familiarize themselves and be prepared to use all available formulations. Patients may not respond to a given opioid or may become tolerant and require rotation to a different one.

Long-acting formulations incorporating special encapsulation or coating or dermal patch are available for various opioids (see Table 6). These include:

  • fentanyl (Duragesic®),
  • morphine (Avinza®, Kadian®, Oramorph®),
  • oxycodone (Oxycontin®), and
  • oxymorphone (Opana ER®).

Fentanyl Dermal Patch

The fentanyl long-acting formulation is only available as a dermal patch. While there is little ability to abuse the fentanyl dermal patch, it is possible to do so by heating it after it is applied to the skin or by freezing a patch and then cutting it into pieces for oral consumption. Unfortunately, some rare patches have been defective and produced overdose deaths resulting in liability claims against the prescribing physician and manufacturer. The major drawback to the fentanyl dermal patch is that initiation of long-acting opioid therapy must be viewed as a lifetime procedure since severe persistent pain with biologic complications is essentially incurable. Can a dermal patch be used for life? Clinical experience is now revealing that many patients require multiple patches for adequate pain relief, and the breakdown of skin with urticarial reaction, itching, and scarring can be formidable.

Morphine

Major cautions with long-acting morphine formulations include their unpredictability, sedation, and constipation. Once stabilized, however, patients maintain excellent pain control.

Oxycodone

The epidemic of oxycodone deaths and diversion for sale calls for great caution. Many of the deaths occurred with relatively low blood levels suggesting that sensitivity, allergy, or drug interactions may have been the terminal event. Physicians who practice in communities with high levels of opioid street abuse should probably avoid prescribing this long-acting opioid due to its history of abuse and to its high monetary street value.

Oxymorphone

The newest long-acting opioid and the one with the least clinical experience is oxymorphone (Opana ER®). To date it has shown a remarkable lack of reported overdose deaths and street abuse. It is unknown as to whether this excellent record will maintain. Oxymorphone is an end product of the metabolic degenerative pathway of morphine, oxycodone, and hydromorphone. Almost all patients on short-acting opioids will, therefore, have already been exposed to it making it less likely to produce an allergic or sensitivity reaction when orally administered. Another safety factor is that it is the only long-acting opioid that produces minimal or no activation of liver enzyme, P450. Consequently—in contrast to morphine, oxycodone, and fentanyl—it escapes rapid deactivation by the liver and, most important, doesn’t enhance blood levels or biologic activity of such drugs as anti-depressants, sedatives, and anti-seizure medications. Practitioners, therefore, appear to have a greater safety profile with oxymorphone than other long-acting opioids. I have found that oxymorphone may not, however, produce much pain relief in some patients likely because it has no active metabolites to bind to multiple receptor types. Also, it may cause dysphoria, nausea, and dizziness that may cause some patients to resist it.

Methadone

Although not a special formulation, methadone is also long-acting. Metha-done carries a special precaution.5 The recent epidemic of deaths associated with methadone are, in part, probablycaused by cardiac conduction abnormalities. Deaths are probably more likely in patients who are already taking antidepressants or other compounds that may also produce cardiac conduction abnormalities.

Table 7. Safety Precautions For Initiation And Maintenance Of Long-Acting Opioid Therapy
  1. Only prescribe long-acting opioids in a structured practice setting where enough time and attention can be given to the patient. Otherwise, refer.
  2. Have a family member or advocate present when a long-acting opioid is initially prescribed.
  3. Educate patient that long-acting opioid therapy may not provide much pain relief for several days and until the dosage is titrated upward to an effective blood level.
  4. NEVER tell patients to totally stop their short-acting opioids and switch to a long-acting opioid. This may cause severe pain flares and withdrawal symptoms forcing the patient to seek relief with uncontrolled, unlabeled use of benzodiazepines, alcohol, opioids, muscle relaxants, and even street drugs.
  5. Don’t try to use an opioid conversion table to totally stop a short-acting opioid and substitute a long-acting opioid.
  6. Follow the patient closely by telephone or in person during the first month and then see the patient about monthly until very stable.
 
   

Initial Dosage And Titration

The initial dosage of long-acting opioid should be quite low even though it may provide little or no pain relief since the patient is already opioid tolerant due to regular use of short-acting opioids (see Table 6). This dosage should be maintained for at least 72 hours to avoid any possible cardiac conduction, allergy, sensitivity, or drug interaction. Once this period has passed, the dosage of long-acting opioid can be progressively raised over the next six to twelve weeks. As the dosage is raised, the patient and practitioner can mutually determine the need and dosage of short-acting opioid for breakthrough, flare pain. The same goes for ancillary medications. The goal is to maximize pain relief while enhancing physical and social functions. There is no maximal dosage of either long or short-acting opioid or ancillary medication. The end point of dosage should always be maximal pain relief without sedation or impairment.

Cautions

Long-acting opioids must be initiated and titrated with great caution to avoid side-effects such as sedation and deaths due to overdose or drug interactions (see Table 7). It is essential that all parties who surround the patient including family, friends, pharmacist, and clergy, among others, be aware that the initiation and maintenance of long-acting opioid therapy likely represents the presence of intractable, life-time pain. Long-acting opioid therapy should be viewed as a serious procedure that will last indefinitely. Certain physicians should avoid long-acting opioids and refer the patient to another physician unless they can structure their practice time to properly educate, titrate, and monitor the patient for adverse complications and maximal pain relief.

Summary

Long-acting opioids are significantly underutilized. Recent attempts by practitioners to use the long-acting compounds, oxycodone and methadone, however, have resulted in an epidemic of drug-related deaths with resultant malpractice and liability suits. A major cause has been practitioners who have instructed patients to totally stop short-acting opioids and substitute a long-acting opioid because they falsely believed they could simply substitute a long-acting opioid. Extensive experience in metha-done maintenance and intractable pain clinics reveal that a much safer and effective method to initiate a long-acting opioid is to leave the current short-acting opioid and ancillary drug regimen in place and initiate long-acting opioid therapy at a low dosage. After 72 hours at a low dosage, the practitioner can then be reasonably assured that any severe complication of drug interaction, allergic sensitivity, cardiac conduction defect, and over-dosage will not occur. After a 72-hour induction period, the dosage of the long-acting opioid can be safely titrated upward over a period of six to twelve weeks. It is recommended that only practitioners who can structure their practice time attempt to use long-acting opioids since they not only have death potential, but also have innate hazards such as sedation and hormone suppression. The patient and family need to be thoroughly educated on the underlying cause of pain and the benefits and hazards of long-acting opioid therapy. When done correctly, long-acting opioid therapy is a godsend for the physical, mental, social, and vocational lives of chronic pain patients. There are now patients in the United States who have survived over 20 years on a combined regimen of long and short-acting opioids.

Last updated on: January 28, 2012
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