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Incredible Story About Opiod Tolerance

Discussion in 'Opiates & Opioids' started by BANGINCOLOR, Sep 3, 2006.



    Reputation Points:
    Feb 18, 2006
    Morphine Hyperalgesia: A Case Report
    George R. Wilson, M.D.,
    Associate Professor and Associate Chairman, Department of Community Health and Family Medicine, University of Florida Health Science Center


    Use of intrathecal infusion has become a mainstay of severe, chronic pain management.1,2 The infusion usually includes an assortment of pharmacologic agents, including anesthetics, opioids and often an a-adrenergic receptor agonist such as clonidine. These combinations have been found to provide excellent pain control with minimal systemic side effects. Several recipes for the infusate, with varying concentrations of each ingredient, are published, thus providing the physician with choices depending on the patient's symptom complex.3

    This case report describes a rare adverse side effect of the opioid moiety of the intrathecal infusate. In this instance it was morphine but this same reaction has been reported to occur with others, such as hydromorphone and sufentyl.4 Review of the literature did not produce specific research data as to the cause for this event but it did uncover a number of case reports5,6,7,8 which help establish this as a genuine adverse event that needs to be recognized. It also underscores a need for research in this particular area of pain management.
    Case Report

    The patient is a 39 year old WM, diagnosed with testicular cancer at age 27. In the intervening 12 years since diagnosis he has had multiple therapies that afforded him a relatively good quality of life. In the summer of 2000 he was enjoying a moderately active lifestyle and was in reasonably good pain control. Pain was controlled (2-3/10) with 200 mg of sustained-relief morphine twice a day. The primary source of pain was extensive metastatic disease to both the spine and lungs.

    During a family trip in November 2000 the patient had sudden severe exacerbation of pain in his low back with loss of strength and sensation in both lower extremities. The pain had a radicular pattern in both lower extremities that was described as "beating, shooting, stressful, squeezing, piercing, constant and terrifying". He rated the pain at a continuous 7/10 and stated that any movement exacerbated the pain to greater that 10/10. Only complete immobility, described by him as being "very, very still", provided any respite. Attempts to control the pain with oral opioids were unsuccessful and, due to the marked severity of the pain and coincident neurologic deficit, he was admitted to the hospital. Evaluation in the hospital with CT scan revealed progression of disease with "…bone destruction at … (L-2) particularly involving the right transverse process." and "residual tumor … compromising the thecal sac…".

    At this point in the course of the disease, the patient was no longer a candidate for surgical, radiological or chemotherapeutic intervention. Efforts to control the pain with IV and oral opioids failed. An epidural catheter was placed and an infusion of morphine, clonidine and bupivicaine was started. This was titrated over several days but there was essentially no change in the patient's level of pain. The discussion started to move toward possible cordotomy and/or necrotizing radiation to the spinal cord. The patient began to express that "If this is the level of pain I have to live with, then I want to die". Large increases in oral and IV opioids provided some relief but not sufficient to change his desire to die.

    After approximately 3-4 days, the epidural catheter was removed and replaced by an intrathecal catheter. The infusate was the same as used with the epidural catheter. The recipe was bupivicaine 0.5%, tetracaine 0.25%, clonidine 20 micrograms/ml and morphine (Duramorph) 6 mg/ml. The initial rate of infusion was 0.5cc/hr. This was gradually increased over the next week to a maximum of 6 cc/hr. On this regimen he did achieve anesthesia and paralysis to the nipple line and it became possible for him to be moved slightly without unbearable pain. Both oral morphine and IV hydromorphone were continued. At this point in the patient's course, hospice was introduced and he was transferred from the hospital to an inpatient hospice facility for pain management and terminal care. Total opioid dose at time of transfer, in oral-morphine equivalents, was 86,000 mg/24hrs.

    On admission to hospice, he was in agonal pain. In addition to continuing his oral morphine and intrathecal infusion, his hydromorphone IV infusion was increased, reaching a maximum dose of 80 mg/hr with 40 mg boluses every 15 minutes. When this failed to achieve pain relief, or even sedation, 20 mg IV boluses of midazolam (Versed) were given approximately every hour. Again neither his pain nor level of consciousness was significantly affected.

    The patient continued to express a very clear and specific wish to die rather than continue with the degree of pain that he was experiencing. His wife supported this request. The decision was made to provide any treatment necessary, short of intentional diaphagmatic paralysis, to obtain pain control, with the very clear understanding that this course of action could result in terminal sedation (double effect principle). It was agreed by all concerned that, due to the extreme degree of suffering that the patient, his wife and his children were enduring, this was an appropriate and ethical course of action.

    Immediately following this agreement, the rate of the intrathecal infusion was increased to 8 cc/hr and the patient was provided intrathecal boluses, as needed, to provide as much pain relief as possible while maintaining the level of anesthesia at or below the nipple line. In addition to the IV hydromorphone, the midazolam was increased to 25 mg every hour. Adjuncts, including IV phenytoin (Dilantin) (100 mg q8hr) and dexamethasone (4 mg q6hr) were added. When this regimen did not provide pain relief a second IV infusion, which was in addition to the hydromorphone, was started. This infusion contained ketamine (2mg/ml), fentanyl (5micrograms/ml) and midazolam (0.1 mg/ml) and was increased over approximately 12 hours to a maximum rate of 15 cc/hr.8 The intrathecal infusion, hydromorphone infusion, and hydromorphone and Versed boluses were continued on an as-needed basis. With this regimen, the patient finally was able to sleep for short periods, although he continued to be easily aroused verbally, and he began to have intermittent periods of pain relief with the boluses of intrathecal infusion. Unfortunately however, over the next 24 hours, these periods of decreased pain and ability to sleep became shorter and shorter. Eventually, on the second day of this regimen, there were only brief periods of pain relief lasting about an hour between boluses. As already mentioned, in spite of the huge and massive doses of opioids and anesthetic agents, the patient remained coherent and conversant throughout the entire process and he continued to ask for help to die.

    A meeting with the patient and his family, with concurrence by telephone of the treating radiation oncologist and hematologist/oncologist, resulted in the decision to proceed with terminal sedation via protocol using a barbiturate infusion. It was decided that this would occur on the following morning to provide the patient, his family and friends an opportunity for good-byes and closure. While it was agreed by all that every possible avenue had been explored, a final call was placed to another institution to review the circumstances of the case and elicit any additional ideas that might be of benefit.

    When the circumstances of this case were described to a pain specialist at this other institution he reported having seen some case reports concerning an adverse response to intrathecal morphine where the total dose per 24 hours had exceeded 25 mg. In the case at hand, at this point in time, the 24-hour intrathecal dose of morphine was at 1,152 mg. Since the decision had been made to proceed with terminal sedation, and since pain control still was not achieved (and was, in fact, getting worse with each hour), it was decided that an attempt to see if this was due to an adverse response to the intrathecal morphine, was warranted.

    The intrathecal infusion was changed to a new formulation with the same concentration of bupivicaine, tetracaine and clonidine but the morphine (Duramorph) concentration
    was decreased from 6 mg/cc to 0.1 mg/cc. The infusion rate was continued at 6cc/hr. Within 6 hours of this change, the pain began to improve. By 12 hours, the patient was no longer requiring any intrathecal boluses. At 24 hours, the hydromorphone infusion began to be decreased and was completely discontinued at 48 hours. Concurrent with this, the ketamine infusion was also discontinued. By 72 hours following the change in the intrathecal infusion, the patient was discontinued from all IV medication, including PRN boluses. Because of concerns for opioid withdrawal, he was placed on a long-acting morphine orally at 100 mg q12hrs. His pain continued to be maintained on intrathecal infusion at a rate of 8 cc/hr. When all other medication was discontinued, the infusion rate was decreased to 6 cc/hr but approximately 12 hours later he required one bolus of 2 cc's so the rate was increased to 7 cc/hr. This rate provided excellent pain control with an anesthesia level mid way between the umbilicus and nipple line. The patient continued pain free with the intrathecal infusion and low dose SR morphine for an additional 6 weeks before dying at home.
    Case Summary

    There are several things that make this case significant, and thus relevant, to End-of-Life care. First is the significant and devastating effect that this man's pain had on his and his family's quality of life. Second was the tremendous quantity of opioids this man received yet he continued to be alert and involved in his own day-to-day care. Third was the apparent speed with which tolerance seemed to develop. Fourth was the apparent lack of response in providing relief of pain from what were, by any standard, huge doses of opioids. Fifth was the apparent adverse and opposite affect that occurred as the dose of morphine was increased.

    When this man's total opioid dose (IV, intrathecal, and bolus) is converted to an oral morphine equivalent, it becomes much clearer and easier to understand the significance these four issues have to pain management. This man, over a period of approximately 96 hours as a hospice inpatient, had his opioid dose (in oral-morphine equivalents) increased from approximately 86,000 mg/24 hours to over 163,200 mg/24 hours. Also, it is important to recognize that, over a 48-hour period, he was weaned down to a maintenance dose of only 1880 mg/24 hours without signs or symptoms of opioid withdrawal.

    This case illustrates several things related to the use of opioids. First, in patients with true physiologic pain, quantity is a very relative issue and not a limiting factor because of concerns over respiratory depression. Second, opioid dose can be increased very rapidly as long as it is done in a controlled and step-wise manner. Third, opioids can be decreased rapidly when pain is controlled and, with minimal precaution, not result in withdrawal. Fourth, increased pain, in the face of adequate increases in opioid dose, may very well be an adverse effect of the drug itself at the receptor level, and not due to the disease process.

    In summary, what becomes clear is that, in spite of rapidly escalated doses of opioids, the period of analgesia that this man enjoyed kept getting shorter and shorter and his pain control was, at best, very poor. Eventually it became apparent that the only relief he received was most likely from the anesthetic agents alone. It certainly was not from the opioids.

    The current theory and understanding of opioid activity defines three major categories of opioid receptors in the central nervous system, m (mu), k (kappa), and d (delta) with two possible subtypes in each category. Analgesia is thought to occur with activation of m receptors, largely at the supraspinal sites, and k receptors within the spinal cord. However, this activation is not specific or consistent. A given opioid drug may interact to variable extent with all three receptors and may vary from pure agonist activity to partial agonist activity or even pure antagonist activity.9 It is this latter potential that is of interest in this case.

    All three receptors (m, k, and d), when activated, appear to function primarily by exerting inhibitory modulation of synaptic transmission in both the central nervous system and the myenteric plexus. Although their location varies, these receptors are often found on presynaptic nerve terminals, where their action results in decreased release of excitatory neurotransmitters. This effect has been demonstrated using both naturally occurring opioids (endorphins) and morphine type drugs. The expected response to binding of these receptors by an opioid, especially binding of the m type, is a marked decrease in pain perception.9

    Research over the last decade is beginning to show a wide variability of the presence and activity of these receptors. In fact, there is very good evidence in mice models, and a growing body of evidence in human studies, that pain perception, and response to opioids (both endogenous and exogenous) has a genetic basis.10 Specific mice studies have shown that the number of m receptors has a direct correlation to the amount of morphine required for pain control.

    The literature has a large number of case reports where pain control has been either extremely difficult or even impossible to achieve or where the response to increased doses of opioids has been contrary to what was expected (such as is described in this report).11 In cases where control has been difficult to achieve, speculation is that these patients were genetically predisposed to a low pain threshold, with few or even absent m receptors.10 However, in cases such as this one, where there is a clear exacerbation of pain with increased dosing, decreased or absent m receptors does not appear to be the cause. Speculation here is that in these cases, the patient develops an excitatory response, rather than an inhibitory response, to binding of the receptors by opioids. In one study involving rats, high doses of morphine produced algesia, hyperalgesia and hypersthesia as opposed to the analgesia found at lower doses. Of even more interest was the fact that these adverse effects were not reversible with naloxone. This suggests that this morphine hyperalgesia may be mediated by a class of receptors similar to that that produces opioid-induced central excitation.12 Rather than decreasing release of excitatory neurotransmitters, they are increased. Review of the clinical course in these cases would suggest that this is not due to a primary defect at the binding site but that it is a secondary response, since it occurs at some point in time after the drug has been used, not with first dosing. The hypothesis is that morphine-related opioids and related metabolites may act via a spinal antiglycinergic effect to reduce postsynaptic inhibition at a non-opioid receptor site, resulting in hyperalgesia.13

    Opioid drugs are metabolized by the liver and excreted by the kidney.14,13 The metabolite of morphine, morphine-6-glucuronide, is much more potent than morphine and while some side effects can be traced to a build up of this metabolite, it does not appear that hepatic or renal failure would explain the reversed effect seen in patients. Also, in this case the patient's hepatic and renal function were completely normal.

    There is sufficient evidence in the literature that supports the concept that there are no significant dose-limiting adverse effects observed in use of morphine.15,2 Specifically, high morphine dosage does not affect patient survival. Some side effects remain relatively constant with morphine usage (constipation) but the majority (sedation, nausea) decline with continued use, regardless of dose.

    Use of opioids, especially morphine, is common in epidural and intrathecal pain control. Opioids pass the blood-brain barrier slowly (more so with morphine and less so with the more lipophilic ones). Placing them in the intrathecal infusion helps minimize this problem. Morphine is used more often because of its low lipid solubility. When placed in the infusion, it spreads throughout the spinal canal and provides good, analgesia that can last from 12-24 hours.2 It's low lipid solubility is an advantage because the more lipid soluble (fentanyl and hydromorphone) have rapid absorption by neural tissues producing very localized effects and segmental analgesia.

    The literature describes a rare "hypersensitivity" type reaction to morphine when the total intrathecal infusion exceeds 25mg in 24 hours.1,2,5,11 How this occurs, and what the relationship is to dose is unknown. Certainly the clinical course of this patient suggests this is what occurred.

    It has long been a recommendation in pain management that patients receiving morphine (or any other opioid) in increasing doses where the desired effect is being seen, that a change to a different opioid be made.5,13 In the more recent palliative care/pain management literature, it is also now a recommendation that, when adverse side effects (such as myoclonus) is occurring, that the dose be decreased. It would certainly seem that this is an appropriate plan, especially in cases where pain control is not being achieved or where pain appears to be escalating out of proportion to the disease process.

    While it is common doctrine among pain management specialist that opioid drugs are not dose limited, a case such as this one suggests that patients not responding as expected, might be experiencing an idiopathic hypersensitivity reaction to the drug. If this could be possible, and the possibility that the escalating pain level is not due to rapidly advancing disease, then consider decreasing or changing to a different opioid drug. `
  2. Fantasian

    Fantasian Gold Member

    Reputation Points:
    Sep 28, 2005
    30 y/o from U.K.
    Very interesting article, i enjoyed it.
  3. acexnx316

    acexnx316 Silver Member

    Reputation Points:
    Jul 10, 2006
    from U.S.A.
    Yeah same here. That was a very intriguing story.