Opioids and the treatment of chronic pain: Controversies, current status, and future directions.

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainly about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinicians' attitudes about prolonged use of opioids and the issue of patient heterogeneity

Despite advances in medical knowledge, sophisticated imaging procedures, and treatment approaches, a significant number of chronic pain patients continue to suffer from unremitting pain. Recently, it has been suggested that opioid analgesics should be used more extensively with this population. This suggestion has resulted in considerable controversy. The preliminary research upon which opioid use for chronic pain patients is based is reviewed and demonstrated to be equivocal. The results of two recent surveys that have addressed physicians' attitudes and prescribing practices for chronic pain patients are discussed. Proposed guidelines for prescribing opioids for chronic pain patients are examined.     

Use of opioids in non-cancer pain

The use of opioids for chronic pain of non-malignant origin remains controversial. However, problems anticipated from experience with animal experiments and pain-free abusers seldom cause difficulties when opioids are used appropriately to treat pain. With sensible guidelines, and in the context of a multidisciplinary pain clinic, opioids may provide the only hope of relief to many sufferers of chronic pain.     

Dose-dependent hypocholesterolaemic effect of oyster mushroom (Pleurotus ostreatus) in rats

Chronic treatment with opioids in cancer patients with chronic intestinal obstruction is hazardous, as uncontrolled constipation may result in definitive bowel obstruction. Intermittent use of opioids adjusted for fluctuating pain levels may enable patients to take the lowest opioid doses that will have sufficient effect, with a consequently lower risk of intestinal side effects. Methadone has many pharmacokinetic characteristics that fit it for use in this clinical situation. In two patients with recurrent episodes of bowel obstruction, methadone used at low doses and at flexible intervals regulated by the patients according to their pain level avoided the occurrence of new episodes of intestinal obstruction. Oral patient-controlled analgesia with methadone may be a simple, safe and cheap method of treating patients with pain associated with subtotal intestinal obstruction.     

Government regulatory influences on opioid prescribing and their impact on the treatment of pain of nonmalignant origin

Interpretation of regulations establishing standards for prescribing opioids by government regulatory boards and drug-enforcement agencies is more restrictive for treatment of nonmalignant pain than for malignant pain. Authority to regulate opioids is provided by health practice acts enacted by state governments, and controlled substances acts, enacted by both state and federal governments. The methods used by boards/agencies to determine standards of practice for opioid use result in interpreting the language in these regulations based on myths, prejudices, and misinformation about opioids, and the unexamined belief that mere exposure of patients to these drugs causes psychological dependence (addiction) on them to all patients in all instances. Interpretation is also strongly influenced by a failure of regulatory and enforcement bodies to recognize their coequal obligation of making opioids readily available to those who need them for legitimate medical purposes, while simultaneously policing their diversion to illegitimate uses. Emphasis on the police function of preventing diversion is paramount. Disciplining practitioners using standards based on myths, prejudices, etc., reinforces physicians' fears of prescribing opioids for nonmalignant pain. Patients with nonmalignant pain who are not relieved if opioids are not provided will continue to suffer until regulatory boards/drug enforcement agencies define the standards of practice for opioid use for nonmalignant pain in clear and unequivocal terms. It is unlikely these standards will be developed until there is a consensus among pain specialists about opioid use for nonmalignant pain because boards/agencies have no consistent, reliable source of expert information. Pain specialists should initiate efforts to develop this consensus.     

Treatment of cancer-related pain: when orally administered medications fail

OBJECTIVE: To summarize the available pain-relieving interventions other than oral medications for cancer-related pain. DESIGN: The pertinent literature is reviewed, and the various options for treating pain in patients with cancer are discussed. MATERIAL AND METHODS: The appropriate situations for use of parenteral administration of opioids, spinal analgesia, neural blockade, and neurosurgical treatment are outlined, and the potential problems and complications associated with these techniques are described. RESULTS: The basic approach to the management of pain in patients with cancer is to begin treatment with less potent analgesic agents early and to progress toward use of more potent pharmaceutical agents, adjuvant drugs, and invasive procedures as needed for alleviation of pain. With parenteral administration of opioids, the dosage can be adjusted rapidly, and therapy can be continued even though a patient may have gastrointestinal dysfunction. A portable ambulatory infusion pump can be used in selected patients. The major advantage of spinal opioid analgesia is the intense analgesia provided with minimal side effects. The potential complications and the availability of treatment alternatives have limited the use of neurolytic blocks, which usually provide only temporary relief of pain. In carefully selected patients with pancreatic or other upper gastrointestinal neoplasms, however, neurolytic celiac plexus and splanchnic nerve blocks are effective. Patients who fail to respond to conservative interventions may be candidates for neurosurgical procedures, such as spinal cord, cortical, or brain-stem stimulation or neuroablative operations (most commonly, cordotomy). CONCLUSION: Cancer-related pain continues to be a major problem, and clinicians should be aware of the availability of effective treatment strategies and techniques. When orally administered medications fail to control pain or cause excessive side effects, patients should be referred to an appropriate specialist or medical center for consideration of other pain-relieving techniques.     

Evaluation of prescription opioids using operant-based pain measures in rats.

Opioids are the most effective compounds available for the relief of pain, yet there are a number of side effects that are of great concern to clinicians. For example, opioids are powerful reinforcers, and the treatment of pain using opioids could lead to the development of addiction. In addition, there is an increasing body of literature demonstrating that the repeated administration of opioids could lead to a phenomenon called opioid-induced hyperalgesia (i.e., increased sensitivity to painful stimulation). Studies examining these potential adverse effects are necessary in the development of novel analgesics. Furthermore, most studies of pain sensitivity and pain relief use reflex-based procedures to identify analgesics; however, it is argued here that operant-based procedures provide measures that are more analogous to the human condition (i.e., the mechanisms of pain are similar to those in humans) and should be useful in the assessment of novel analgesics. A series of studies examining the effects of opioids and the influence of variables such as age are discussed to demonstrate the utility of this approach. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A review of the effects of opioids on psychomotor and cognitive functioning in humans.

The literature on the effects of opioids on psychomotor and cognitive functioning in humans is evaluated. Some studies have examined the acute and chronic effects of various opioids on different subject populations. In addition, epidemiologic studies have examined the neuropsychological functioning and the risk of accidents for persons who have (or have had) opioids in their systemic circulation. In general, it appears that some opioids (mixed agonist-antagonists) more than others (morphine or codeine) impair psychomotor and cognitive functioning in healthy volunteers who have no history of opioid abuse. However, perhaps because of tolerance mechanisms, those who use opioids occasionally or habitually (patients with chronic pain or opioid abusers) are much less likely to have impairment of psychomotor or cognitive processes by opioids. Past research and present gaps in knowledge are used to make recommendations regarding worthwhile future directions in research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age, pain intensity, and opioid dose in patients with advanced cancer

BACKGROUND: Elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, but an association between age and long term opioid consumption has not been established clearly in patients with advanced cancer. METHODS: The computerized records of 197 cancer patients admitted to a palliative care unit in Edmonton, Alberta, Canada were examined. The authors examined: demographics (age, gender, and location of primary tumor), pain characteristics (presence of neuropathic pain and incidental pain), mean daily pain intensity (MDPI), and daily opioid consumption measured as (parenteral) morphine equivalent daily dose (MEDD). MDPI and MEDD were assessed on Days 2 and 7 after admission, on the day of maximum opioid consumption, and on the day of maximum pain intensity during admission. Average values for MDPI and MEDD were calculated between Days 2 and 7. RESULTS: When age was treated as a categoric variable (< 65 years, 65-74 years, and 75+ years), statistically significant differences in MEDD were observed for age for all estimates except those for Day 7, with older patients requiring a lower equianalgesic dose. No major differences were observed for pain intensity and for the presence of incidental or neuropathic pain across the different age groups. In the multivariate analysis, the reduction in MEDD ranged between 27-71 mg when patients age > or = 75 years were compared with younger adults. A MEDD increase that ranged between 82-137 mg was associated with the presence of neuropathic pain. CONCLUSIONS: The current study suggests that elderly cancer patients may experience a similar level of pain intensity but require a lower amount of opioid analgesia than younger adults. However, because elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, opioids should be initially administered at a lower dose and titrated cautiously in these patients.     

AgNOR mark epithelial foci in malignant transformation in hamster cheek pouch carcinogenesis

Research demonstrates that many nurses lack knowledge about pain assessment, the differences between acute and chronic pain, and the use of pain rating scales. In this article, the authors describe an instrument for evaluating chronic pain, the purpose of which is to assess systematically the various dimensions of chronic pain and its impact on quality of life. This assessment can establish a baseline for developing clients' treatment plans and can be used to evaluate the effectiveness of treatment plans. Using this tool can provide an accurate multidimensional assessment of clients' chronic pain experiences. The article also discusses recommendations for other applications of the tool.     

Comparison of urinary bone resorption markers in women of 40-70 years; day-to-day and long-term variation in individual subjects

Pethidine is an effective epidural opioid for the treatment of acute pain. Its use has been well described in Australian and New Zealand practice, particularly in the field of obstetric anaesthesia. Reported methods of delivery have included bolus injection, continuous infusion and patient-controlled epidural analgesia. Areas of application have included treatment of postoperative pain, labour pain and intraoperative pain. Because of its intermediate lipid solubility, pethidine may have advantages over many other epidural opioids. However, potential for accumulation of norpethidine limits its use to relatively short durations of treatment.     

Propentofylline inhibits production of TNFalpha and infection of LP-BM5 murine leukemia virus in glial cells

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.     

Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization

Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous system. Clinical pain states with allodynia in connection with longstanding superficial wounds have, however, not been reported in the literature. In this case a chronic pain state developed in a previously healthy 17-year-old girl in and around a persistently suppurating appendectomy wound. There was no spontaneous pain but pronounced allodynia in the wound and in the surrounding skin. Quantitative thermal tests showed abnormal thresholds for several sensory modalities confirming abnormal processing of sensory input from the involved area. The pattern of sensory abnormalities evaluated with thermal testing changed transiently and the allodynia diminished during a phentolamine block. Since the pain responded poorly to opioids and ketamine has been reported to reduce allodynia, it was administered in a sub-dissociative bolus dose during wound dressing. The wound was essentially unchanged after treatment for 3 months but the allodynia and sensory aberrations had decreased significantly. We interpret these results as a de-sensitizing effect in the long term of repeated NMDA-receptor blockade by ketamine in a chronic pain state, with indications of central sensitization, partially maintained by sympathetic activity.     

Intrathecal opioids for the control of pain experienced during labor and in the post-cesarean section period

Since the discovery of opiate receptors in the brain and spinal cord, considerable research has been performed to include intrathecal opioids for the control of pain. No area has used this knowledge more than the practice of obstetrical anesthesia. Intrathecal opioids have been shown to be very effective in controlling the pain experienced in the first stage of labor but have been ineffective in controlling second-stage labor pain. Intrathecal opioids, especially morphine sulfate, provide long-term analgesia but are associated with a high number of side effects. Research studies have attempted to determine the optimal dose of intrathecal opioids to provide the greatest amount of analgesia with the lowest incidence of side effects. Intrathecal morphine sulfate has been shown to be effective in controlling first-stage labor pain but has been shown to be the most efficacious in controlling the pain experienced in the post-cesarean section period. This article reviews the current literature and provides background of information to understand these developments.     

Malignant bone pain

Bone pain is one of the most frequent causes of pain in patients with cancer, and the levels of metastases and bone pain are not directly correlated. Nociceptors in the periosteum are probably stimulated by halisteresis or by inflammatory oedema leading to an increase in the intraosseous pressure. Some authors believe that the nociceptors in bone are mediated via intraosseous mechanoreceptors in the bone-matrix. At a low pain level the initial treatment is acetylsalicylic acid, paracetamol or other nonsteroidal antiinflammatory drugs. At increasing pain level initial doses of oral opioids are added. In severe bone pain, where conventional therapy seems difficult, opioids are administered by invasive techniques. In localised bone pain palliative radiation is the first treatment of choice. Corticosteroids induce an analgetic effect indirectly by reducing the inflammatory oedema, inhibiting the synthesis of prostaglandins and may inhibit excitatory nerve fibres. Endocrine treatment, calcitonin and biophosphonates have shown a documented pain-relieving effect in patients with disseminated breast and prostate cancer. Chemotherapy has shown a pain-relieving effect in patients with disseminated breast cancer, surgical intervention is used in stabilizing osteolytic bones before or after a fracture ensuring a reasonable relief of pain.