My patient with rectal cancer does not have pain control despite high doses of opioids and optimal doses of gabapentin and desipramine. Now what?-advanced strategies for cancer pain management

Patients with cancer pain may expect pain relief from noninvasive therapy in 80% to 90% of the cases. Thus, in 10% to 20% of the patients, intraspinal therapy will be needed. This article reviews the alternative techniques and medications for intraspinal therapy for patients who failed to experience full pain control from aggressive pharmacologic therapy. Moreover, factors to consider in the decision to implement one of the techniques for long-term pain management are discussed. Protocols that we have implemented in our institution for intraspinal therapy are presented, and alternative drugs for patients who do not respond to this approach are discussed. In our expericence with this approach, virtually all patients may experience pain relief from cancer. Copyright © 2000 by W.B. Saunders Company     

Cellular mechanisms of opioid tolerance and the clinical approach to the opioid tolerant patient in the post-operative period

The high prevalence of opioid use for recreational purposes in the USA and the European Union, as well as the use of opioids for the treatment of chronic non-malignant pain, has resulted in an increase in the number of patients with opioid tolerance who undergo surgery and require post-operative pain management. The approach to post-operative pain control in these patients is significantly different to the strategies used in opioid naïve patients. Fortunately, better understanding of the cellular mechanisms of opioid tolerance in animals has resulted in the transfer of concepts from the ‘bench’ to the clinical arena. This chapter describes the new developments in opioid tolerance and how this knowledge can be applied to clinical practice.     

Intraspinal morphine for cancer pain

From a survey of the recent literature on chronic intraspinal morphine administration for cancer pain concerning 412 cases, the present authors observe that: 1. data regarding follow-up on pain relief and complications are lacking; 2. continuous administration by closed systems shows more efficacy in long-term pain relief; 3. tolerance, although not reported by all authors, is present and becomes remarkable in prolonged administration; 4. serious side-effects are less frequent with the epidural administration technique. These data are confirmed by the present authors' clinical experience of 22 patients treated with epidural morphine administration and 53 patients treated with intrathecal morphine. The widespread use of these methods is limited not only by technical complications but also by the existence of certain types of pain which do not respond to morphine and which may develop, as part of the evolution of the neoplastic disease, even during treatment with intraspinal morphine.     

Psychomotor and cognitive functioning in cancer patients

Psychomotor and cognitive dysfunction in cancer patients can be classified into two main categories according to etiology: disease-induced factors (metabolic disturbances, brain metastasis, pain, etc.) and treatment-related factors (drugs, antineoplastic therapy, etc.). In particular, the effects of chronic opioid administration in cancer patients have been subjected to investigations, and most studies have been engaged in assessment and treatment of the cerebral dysfunction. Early studies found that cancer patients in chronic oral opioid therapy had prolonged continuous reaction times, and that the opioids seemed to be mainly responsible for the prolongation. Significant dose escalations of opioids (≥ 30%) caused transiently impaired psychomotor and cognitive functions in cancer patients. Cancer patients in chronic oral opioid therapy did not achieve any advantages changing to epidural opioid therapy with regard to faster continuous reaction times and less pain.
Large doses of opioids are often required to control severe pain in cancer patients. As increased sedation and impaired psychomotor and cognitive functions often occur, a number of studies have investigated the use of amphetamine derivatives to counteract the sedative side-effects of opioid. These drugs seem promising during high-dose opioid therapy and their use may be particularly rewarding in poor opioid-responsive pain conditions such as incident and neuropathic pain.     

Opioid therapy for chronic noncancer pain: practice guidelines for initiation and maintenance of therapy

Contemporary standard pharmacological care for the treatment of noncancer pain includes the use of opioid medications. The responsiveness of neuropathic pain to opioids has long been an area of controversy. Evidence from multiple randomized controlled trials indicates that opioids can relieve pain in a variety of neuropathic pain syndromes. Opioids are typically reserved for moderate to severe pain that cannot be relieved by the nonsteroidal anti-inflammatory drugs (NSAIDs). Opioids are often used in combination with other adjuvants or other analgesic agents. The advantage of opioids is the lack of a ceiling effect of the pure mu opioid agonists. The disadvantages of these drugs are a series of mechanism-based opioids-related side effects (e.g., nausea, drowsiness, constipation) and the potential issue of their abuse and misuse. Each patient needs to undergo a comprehensive evaluation and receive education on the treatment. The physician must be well conversant with the differential diagnosis and definitions of physical dependence, tolerance, pseudotolerance, aberrant behaviors, addiction, and pseudoaddiction. No specific opioid drug is intrinsically 'better' than the others. Opioid rotation refers to the switch from one opioid to another when the degree of analgesia obtained is limited by the persistence of adverse effects or the occurrence of clinically relevant tolerance. This approach is based on the observation that a patient's response varies from opioid to opioid. At present, after 1) appropriate selection of patients and 2) longitudinal patient care with routine assessment of degree of analgesia, functional daily activities, adverse events and aberrant behaviors is carried out, opioid therapy can be the safest and most effective treatment measure for quality of life improvement in the chronic pain patient.     

Aufmerksamkeitsbelastung und Reaktionszeiten unter Opioiddauertherapie Ein Vergleich mit chronischen Schmerz- patienten und mit Nichtschmerzpatienten

Objectives: Despite increasing use of oral opioids in cancer and non cancer pain, little is known about the effects of long-term opioid therapy on psychomotor performance. This study was designed to investigate the effects of long-term opioid analgesia on attention and reaction time in cancer pain and in non-malignant pain. Methods: Three groups of patients (n=128) were studied: 48 patients on long-term opioid therapy (group O; including 33 patients with cancer pain and 15 patients with chronic non-malignant pain), 30 patients receiving non-opioid analgesic therapy for chronic non-malignant pain (group NO) and a control group (group K) of 50 patients without pain and analgesic therapy. Attention was determined by Brickenkamp’s d2-test, continuous reaction time by Schuhfried’s method (Wiener Determinationsgerät, Mödling, Austria). In addition, a modified questionnaire developed by Zerssen was used to determine the patient’s current mood. Pain, fatigue and anxiety levels were estimated by visual analogue scales. Results: Although no significant difference in attention/concentration could be demonstrated between the three groups, patients taking opioids performed Brickenkamp’s test a little worse and also demonstrated a significant decline in this parameter with advancing age. Also, in cancer patients attention/ concentration was more impaired than in non-cancer opioid patients. Auditory and optical reaction times were significantly slower in patients on opioids than in the non-opioid analgesic group and highly significant slower than in the control group, while in the more complex combinations test no such difference could be demonstrated. In addition, a highly significant deterioration in reaction times with increasing age could be demonstrated for opioid patients compared to the other groups, while only a non significant prolongation was found between cancer and non-cancer patients on opioid therapy. Conclusions: Long-term opioid therapy produces a slight (non significant) impairment of psychomotor performance in patients with cancer pain or non-malignant chronic pain. These effects become significantly more pronounced with increasing age and in patients with cancer pain, indicating a higher susceptibility of the elderly towards opioids. These results indicate that, particularly in older patients receiving long-term opioid for cancer oder non-cancer pain, careful evaluation of their effects on psychomotor function is necessary in order to estimate patient’s ability to perform his daily activities. However, since opioid effects were only minimal in the non-elderly other factors like basic disease, opioid dose, physical condition and age seem to be of greater importance than the effects of opioids per se.     

Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients

A survey of all patients (173 males and 294 females) registered with primary intraspinal neoplasms in the Norwegian Cancer Registry from 1955 through 1986 is presented. Annual age-adjusted incidence rates of new tumors per one million population were three for males and five for females. Altogether, 89% of the tumors were verified histologically. Meningioma was the most common tumor type, followed by ependymoma and neurilemoma. Intraspinal ependymomas accounted for 34.5% of all 223 ependymomas of the central nervous system, whereas only 0.2% of the 3046 glioblastomas were found intraspinally. Patients with intraspinal meningioma had a better life expectancy than those with intracranial meningioma. The 5-year relative survival rate for patients with intraspinal ependymoma was 88.9% in contrast to 24.4% for patients with intracranial ependymoma.     

Treatment of pain in the oncologic patient

Around 65-85% of cancer patients suffer from pain at advanced stages. Pain is often inadequately treated, although it can be controlled simply in the majority of cases. It is important to try and achieve a number of targets, including pain control at night, resting pain and pain during movement. Pain can be divided into somatic pain caused by the stimulation of traditional nociceptors, visceral pain and neuropathic pain caused by damaged nervous fibres. All three types may exist in the same patient. Drugs are the main method used to control oncological pain. The three main classes of drugs (FANS, opioid analgesics and adjuvant analgesics) are used individually or in combination. Given that the collateral effects of opioid analgesics may limit their value, they must be monitored to ensure careful treatment. The appropriate use of invasive treatment in patients with advanced disease who do not respond to oral therapy may alleviate cancer pain in 10-30% of cases. These adjuvant procedures are classified as blockades of autonomous nervous tissue, peripheral nerves and neuraxis. In conclusion, the ability to give an overall evaluation of a patient with pain, to ensure the component administration of analgesic drugs and to inform the patient and the family forms the basis of the treatment of pain in cancer.     

Recent advances in pain management in palliative care

Pain causes significant morbidity in cancer patients. The total pain experienced by these patients encompasses physical, social, spiritual and psychological dimensions. A multidisciplinary approach is essential in their effective management. Following simple well-established guidelines the majority of cancer pain can be controlled; however, there is evidence that these guidelines are not well adhered to and that many patients have unnecessarily poorly controlled pain. This article looks at the background principles underlying effective pain management before examining how recent advances in neurophysiology and pharmacology have broadened our options in the use of opioid and adjuvant analgesics.     

Analgésie par site implantable pour injections intrathécales itératives de morphine

The use of intraspinal narcotics has been widely accepted as pain relief treatment for intractable cancer pain. Intraspinal low doses of morphine induce a potent selective long lasting analgesia. To avoid repetitive lumbar puncture, a drug delivery device was surgically implanted in 41 patients. The surgical procedure is described. The mean amout of morphine needed was 1.48±0.25 mg per day at time of surgery, rising to 6.86±1.47 mg per day after a mean survival time of 65 days. Tolerance became a major problem in 18 patients, which nearly all were selected at a late disease stage and previously received narcotics for pain relief. However, no clear-cut prognostic factor had a predictive value for the appearance of tolerance. In some cases, it could be successfully treated by intraspinal injection of local anaesthetics or clonidine. CSF leakage was noted in 11 patients; this was a challenge for us, as no other authors reported such a high rate for this complication. Aseptic meningitis was noted three times. In all cases but one, the symptoms resolved with appropriate treatment.     

Interventional approaches to pain management

This article reviews the evidence for several common interventional techniques for the treatment of chronic pain, including: intraspinal delivery of analgesics, reversible blockade with local anesthetics, augmentation with spinal cord stimulation, and ablation with radiofrequency energy or neurolytic agents. The role of these techniques is defined within the framework of a multidisciplinary approach to the neurobehavioral syndrome of chronic pain. Challenges to the study of the analgesic efficacy of procedural interventions are explored, as are the practical issues raised by their clinical implementation, with the aim of helping nonspecialist physicians identify the patients most likely to benefit from these approaches.     

Successful use of methadone in the treatment of chronic neuropathic pain arising from burn injuries: a case-study

Methadone is used increasingly as a second-line opioid in the management of cancer pain refractory to conventional opioids. Recent case studies suggest that its use as an analgesic could be extended to non-cancer pain, especially neuropathic pain. The present case study reports, for the first time, the efficacy of methadone in a burn patient experiencing neuropathic pain in his healed wounds. The patient sustained extensive (55% total body surface area) chemical burns and developed chronic burning sensations, particularly in the lower limbs where skin grafting had been performed. Conventional pharmacotherapies against neuropathic pain were attempted to control pain for over 5 years. The agents used included long- and short-acting opioids, amitriptyline, clonazepam, and gabapentin, but they all failed to relieve the pain. When methadone (5 mg every 12 h) was introduced, it significantly alleviated the patient's pain within a few days of administration. The patient has now been taking methadone (15 mg every 12 h) for 10 months and reports that the opioid caused 70% pain relief and a 55% amelioration in his quality of life. Although these results are based on a case report, they suggest that a switch to methadone might be useful in some burn patients who have developed chronic neuropathic pain unrelieved by conventional pharmacotherapies. Methadone, however, needs to be titrated with vigilance and thus should be administered by a physician experienced with its use in the treatment of chronic pain.     

Postoperative Analgesia in Morbid Obesity

Morbidly obese patients due to high incidence of obstructive sleep apnea (OSA) are predisposed to opioid induced airway obstruction and thus frontline high ceiling analgesics (opioids) have concerns based on safety in their liberal use. Although surgical techniques over the last two decades have seen a paradigm shift from open to laparoscopic procedures for morbidly obese patients; optimally titrated yet safe analgesic management still remains a challenge. The present review sums up the analgesic options available for management of morbidly obese patients undergoing surgery. We highlight the utility of multimodal approach for analgesia with combinations of agents to decrease opioids requirements. Pre-emptive analgesia may be additionally used to improve the efficacy of postoperative pain relief while allowing further reductions in opioid requirements.     

Continuous brachial plexus block at the cervical level using a posterior approach in the management of neuropathic cancer pain

BACKGROUND AND OBJECTIVES: Neuropathic cancer pain due to tumor growth near the brachial plexus is often treated with a combination of nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, anticonvulsants, and oral or transdermal opioids. We propose placement of a catheter along the brachial plexus using a posterior approach for patients not responding to the above-mentioned treatment. CASE REPORT: We describe 2 patients with neuropathic cancer pain in the arm and shoulder despite treatment with dexamethasone, amitriptyline, gabapentin, opioids, and, in 1 patient, oral ketamine. An increase in daily opioid dosage did not relieve the pain but caused unacceptable side effects of nausea, vomiting, and sedation. Continuous administration of local anesthetics via a brachial plexus catheter inserted at the cervical level using a posterior approach resulted in a markedly improved analgesia and decreased opioid requirement. CONCLUSION: Continuous brachial plexus block should be considered in patients with severe neuropathic cancer pain in the arm and shoulder. To achieve sufficient pain relief for prolonged periods of time, a catheter was inserted to block the brachial plexus using a posterior approach. This technique may be a valuable alternative to the interscalene approach because of the improved fixation of the catheter in the muscle sheet of the trapezius, splenius cervicus, and levator scapulae muscles, and the decreased likelihood of catheter dislodgment during neck movements.     

Analgesia with an implanted device for repetitive intrathecal injections of morphine

The use of intraspinal narcotics has been widely accepted as pain relief treatment for intractable cancer pain. Intraspinal low doses of morphine induce a potent selective long lasting analgesia. To avoid repetitive lumbar puncture, a drug delivery device was surgically implanted in 41 patients. The surgical procedure is described. The mean amount of morphine needed was 1.48 +/- 0.25 mg per day at time of surgery, rising to 6.86 +/- 1.47 mg per day after a mean survival time of 65 days. Tolerance became a major problem in 18 patients, which nearly all were selected at a late disease stage and previously received narcotics for pain relief. However, no clear-cut prognostic factor had a predictive value for the appearance of tolerance. In some cases, it could be successfully treated by intraspinal injection of local anaesthetics or clonidine. CSF leakage was noted in 11 patients; this was a challenge for us, as no other authors reported such a high rate for this complication. Aseptic meningitis was noted three times. In all cases but one, the symptoms resolved with appropriate treatment.     

Tumorschmerztherapie

Pain belongs to the most prevalent symptoms that require patients with urological tumours to seek medical help. The treatment of cancer pain requires standardized guidelines that are best reflected by the WHO’s three-step ladder of cancer pain relief. This implies an individualized approach, a detailed history taking of underlying pain and thorough clinical examination, as well as a consistent and forceful therapy of constant and breakthrough pain episodes, using pharmacological substances and non-pharmacological techniques. This requires the choice of the correct drug, an application “by the clock”, an individualized dose titration, and the use of co-analgesics. For constant “background” pain, slow release substances are needed, whilst fast acting pain medication is given on demand for breakthrough pain episodes. Besides symptomatic analgesic therapy, cancer pain therapy may also comprise tumor specific treatment modalities, whenever appropriate and requested by the patient. This comprises radiation therapy, e.g. for bone or soft tissue processes or brain metastases, as well as radionuclide techniques, surgical procedures, chemotherapy, new substances or antihormonal therapy. Furthermore, pain is considered a multimodal experience that requires the consideration of psychical and social factors. This chapter describes the different facets of cancer pain, its epidemiology, pathophysiology, diagnostics and therapeutic principles.     

Opioid responsiveness

Cancer pain generally responds in a predictable way to analgesic drugs and drug therapy is the mainstay of treatment. A small proportion of patients, of the order of 20%, have pain that does not respond well to conventional analgesic management. Because opioid analgesics are the most important part of this pharmacological approach, a terminology has developed which centres around whether or not pain will respond to opioid analgesics. The terms opioid-responsive-pain and opioid-non-responsive pain, or opioid-resistant-pain, have been used to differentiate between patients whose pain falls into these two broad groups. This terminology is not satisfactory because it implies an all or none phenomenon, that is that pain either does or does not respond to opioid analgesics. Rarely is there such a clear distinction in practice. This is because the end point when titrating dose against pain with strong opioid analgesics is not simply pain relief or lack of relief: adverse effects may limit dose titration. It is preferable to describe patients with pain which is relatively less sensitive to opioids and/or patients where there is an inbalance between analgesia and unwanted effects as having “opioid-poorly-responsive pain”. A pragmatic definition of opioid-poorly-responsive pain is pain that is inadequately relieved by opioid analgesics given in a dose that causes intolerable side effects despite routine measures to control them. Included in this definition is so called paradoxical pain which is not a distinct entity. Neuropathic pain is the most common form of opioid-poorly-responsive pain. The underlying pathophysiology remains unclear but abnormal metabolism of morphine is not the cause of a poor response to this drug. Patients with opioid-poorly-responsive-pain should be considered for treatment with the same opioid by an alternative (spinal) route or with an alternative opioid agonist administered by the same route (whether oral or parenteral), in conjunction with adjuvant analgesics such as tricyclic antidepressants. The most commonly used alternative oral opioids are phenazocine and methadone; transdermal fentanyl is an additional option.     

Efficacy of the world health organization analgesic ladder to treat pain in end-stage renal disease

Pain is the one of the most common symptoms experienced by patients with ESRD; it impairs their quality of life and is undertreated. Most pain clinicians believe that the pain management approach of the World Health Organization (WHO) three-step analgesic ladder is applicable to the treatment of patients with ESRD, but this approach has not been validated for them. A cohort of 45 hemodialysis patients were assessed for type and severity of pain using the Short-Form McGill Pain Questionnaire and then treated during a 4-wk period according to the WHO analgesic ladder. Mean age was 65 +/- 12.5 yr, and 22 (49%) patients had diabetic nephropathy as the cause of ESRD. Initial pain was rated severe by 34 (76%) patients. There was no difference in initial pain rating by gender, age, race, or type of pain. Forty percent of patients reported nociceptive pain, 31% neuropathic, and 29% both. Adequate analgesia was achieved in 43 (96%) of 45 patients. The mean pain score decreased from 7.8 +/- 1.2 to 1.6 +/- 1.3 (P < 0.001). Patients who were 65 yr and older had higher posttreatment scores than those who were younger than 65 (2.1 +/- 1.4 versus 0.94 +/- 0.93; P = 0.002) and more medication adverse effects. It is concluded that the use of the WHO three-step analgesic ladder leads to effective pain relief in hemodialysis patients. Older patients will need more careful pain management to achieve the same results as younger patients. Further studies are needed to confirm these results in a larger, more diverse dialysis population.