E PIDURAL A NALGESIA For major thoracic and abdominal surgical procedures, epidural analgesia is superior in its pain-relieving effects when compared to other analgesic therapy. Evidence from a recent meta-analysis on postoperative epidural analgesia confirms that better pain con- trol is achieved compared to parenteral opioids regardless of the analgesic agent and level of the catheter. 41 The optimal approaches for this technique are often debated as epidur- al analgesia can involve both single agent or combination therapy and delivery of agents at different levels in the epidural space. Moreover, variations exist in reported failure rates and risk/benefit analyses. Most often therapy with continuous infusions with or without patient-controlled epidural analgesia is associated with better pain outcomes than intermittent dosing schedules alone. Studies consistently show that combinations of an opioid and local anesthetic provide significantly greater pain relief following upper and lower abdominal surgery in contrast to single agent administration. The advantages of lipophilic opioids (fentanyl and hydromorphone) alone are questionable, especially for pain management after upper and lower abdominal procedures. 42 There is definitely a role for epidural analgesia following major abdominal surgery for GI malignancies. Despite the lack of randomized controlled trials to evaluate the effectiveness of catheter levels with abdominal procedures, the use of thoracic epidurals remains the standard for practice. The key is concordance of anatomic site and catheter location (ie, thoracic dermatome incision and thoracic epidural). With opioid and local anesthetic combinations, thoracic administration promotes the drug delivery of smaller doses of lipophilic agents at the same level of the incision and lessens chances for motor and sympathetic blockade from local anesthetics. 42 Successful placement of thoracic catheters requires technical expertise that is often present among pain management trained anesthesiologists or general anesthesiologists with extensive experience. Along with the level of catheter placement, the selection of an opioid and local anes- thetic combination solution and hourly rate of administration seem to be the most important determinants of treatment success with epidural analgesia. The mechanism of action of epidural opioids is by mu receptor activity in the spinal cord and systemic absorption. Fentanyl, because of its lipophilic pharmacological property, provides more segmental pain relief and is probably effective through absorption into the systemic cir- culation. Epidural doses often approximate those required for systemic administration. While fentanyl causes less pruritis and nausea compared to morphine, which has some advantage in patients with GI malignancies already experiencing preoperative nausea, its limited vertical distribution may lead to less effective pain control with extensive abdom- inal incisions when administered through lumbar catheters. Morphine, because of its hydrophilic properties, has greater rostral (vertical) spread in the epidural space, thus it is more appropriate for managing pain from surgical incisions that are more remote from the catheter tip. Hydromorphone, used less often, provides similar relief as morphine with limited side effects. Approximately one-fifth to one-fourth of the systemic dose is required for epidural morphine and hydromorphone administration; therefore, addi- tional systemic opioids may be needed to abate physiological withdrawal in opioid- dependent patients. Bupivacaine, in concentrations of 0.065% to 0.125%, is the most common local anesthetic for postoperative epidural analgesia solutions, and levobupivacaine and ropi- vacaine are less often used. Motor blockade is more common with bupivacaine and lev- obupivacaine, while ropivacaine in typical doses is selective for sensory blockade only. Patients receiving local anesthetics should be observed for sensory impairment below the 206 Chapter 12 Ch12.qxd 4/6/2005 4:27 PM Page 206 catheter level including routine inspection of the skin, repositioned frequently to allevi- ate pressure, given range of motion exercise to improve circulation and prevent throm- bophelebitis, and assisted when getting out of bed. Adjustments in infusion rates, typi- cally a decrease of 20 to 25%, changes in the concentration of local anesthetic or switch- ing the local anesthetic to ropivacaine can prevent moderate to dense motor blockade. Complication rates for epidural analgesia include dural puncture (0.32% to 1.23%), direct neurological trauma (extremely rare), spinal hematoma from puncture of epidur- al vessels during catheter insertion (3% to 12%), catheter migration (0.15% to 0.18%), and infection (extremely rare). Respiratory depression (respiratory rate <8 per minute), while the most serious, is no greater than the incidence associated with systemic opi- oids. 42 Patients closely followed by acute pain management services are less likely to experience respiratory depression, and frequent monitoring of respiratory rate and cau- tious use with older patients >70 years of age and those with pre-existing respiratory dis- eases can often prevent its occurrence. Pruritis, which is a less serious adverse effect but more distressing to patients, occurs in about 40% of patients, more commonly with morphine. Small intravenous doses of naloxone (<0.1 mg) administered IV every 2 to 3 hours is the most effective treatment. CHRONIC PAIN MANAGEMENT C ANCER P AIN S YNDROMES Patients with cancer may also experience pain from pre-existing or new chronic non- malignant pain syndromes. Regardless of the etiology, cancer pain can be classified as somatic, visceral or neuropathic, or mixed pain syndromes including any combination of these physiological sources. In an international study involving a sample of over 1000 patients with severe cancer pain, 71.6% were found to have a component of somatic pain, 39.7% visceral pain, and 34.7% neuropathic pain. 43 Clinical assessment of cancer pain syndromes, whether related to cancer treatment or disease progression, begins with identifying the cause and determining the likelihood for worsening. Early aggressive intervention to gain control of the pain should always be attempted, especially for patients who present with pain as a symptom of advancing dis- ease. In fact, palliative or supportive care should be initiated earlier rather than later so that multiple approaches to relieving pain and symptom and emotional distress have the greatest chance to ameliorate needless suffering and maximize quality of life. To help physicians’ understand suffering, Chapman and Gavrin elucidate its meaning to patients and clarify that pain is not synonymous with suffering. 44 While pain is one cause, suf- fering is much less tangible and spans a person’s entire existence. Referrals to palliative care can be difficult as this often requires confronting the realization that it may not be possible to control or reverse tumor progression and communicating this to patients. Palliative care has evolved not only as an approach to assist patients to die, but also to help them live. Unlike hospice care, fewer restrictions are placed on treatment and aggressive interventions with palliative services so patients can still receive active thera- py for their cancer. Treatment-Related Pain Syndromes Cancer treatment-induced pain syndromes that might be associated GI malignancies include postsurgical syndromes (eg, postthoracotomy syndrome), postradiation syn- The Assessment and Management of Acute and Chronic 207 Ch12.qxd 4/6/2005 4:27 PM Page 207 dromes (radiation-induced lumbosacral plexopathies, enteritis and proctitis, burning perineum, and osteoradionecrosis), and chemotherapy-induced (painful peripheral neu- ropathy and plexopathy associated with intraarterial infusion, and hepatic arterial infu- sion). Cancer-Related Pain Syndromes S OMATIC P AIN Somatic pain, the most common form of cancer pain, arises from nociceptor activa- tion in the skin, subcutaneous tissue, bones, blood vessels, and muscle. It is generally well localized; however, bone and muscle pain can be more diffuse. The bone is the most frequent site for metastasis, accounting for over 40% of pain syndromes associated with cancer progression. 43 Skeletal involvement occurs less often with advanced gastrointes- tional malignancies compared to primary cancers of the breast, lung, kidney, and prostate. Tumor invasion of bone is associated with intense pain, especially on move- ment, which can significantly compromise mobility. Of 108 patients presenting to a multidisciplinary pain clinic for bony metastases, 79% reported moderate to severe pain on average and, after examining their treatment plans, investigators concluded that the majority required more aggressive pain therapy than what was prescribed. 45 Severe mus- cle spasms may occur in the areas of the lesions over unstable vertebral bodies or long bones. Serious and painful complications of bony metastases include pathological frac- tures, compression fractures, and nerve root compression. Treatment approaches for bony metastases include pharmacotherapy, surgical inter- vention for stabilization, chemotherapy and radiation therapy, and radioisotopes; how- ever, the indications and effectiveness of many treatment strategies are tumor-depend- ent. Recently, a systematic review of randomized studies showed that single fraction radi- ation is just as effective as multifraction radiotherapy in relieving pain; however, retreat- ment rates (21.5% vs 7.4%) and pathological fractures (3% vs 1.6%) were higher in patients who received single fraction treatment plans. 46 NSAIDs may be helpful initial- ly alone or combination with opioids, but typically when patients require higher doses of opioids the added risk for adverse effects may outweigh the benefits. Flexible sched- ules for opioid analgesia should be prescribed to allow patients to self-medicate for episodic pains associated with activity. If long-acting opioids are used, adequate rescue medication with short-acting opioids should be prescribed for breakthrough pain. A variety of pain-elieving agents exert their pharmacological actions by specifically targeting mechanisms of cancer-mediated pain both systemically and at the site of tumor infiltration. These include tumor necrosis alpha receptor antagonists, osteoclast inhibitors, inhibitors of glutamate release, substance P inhibitors, nitric oxide synthetase inhibitors, and other novel compounds. 28 Consult the following references for more detail on the mechanisms and treatments for bone pain. 47,48 V ISCERAL P AIN Pain arising from nociceptors in the organs and those that line the organs and body cavities constitutes visceral pain. Tumor invasion of viscera often results in painful stim- uli that cause stretching or enlargement, especially of hollow viscera, and inflammation. Cervero describes the five major characteristics of visceral pain: 1) is not evoked from all viscera, 2) in not linked to visceral injury, 3) causes referred pain, 4) is poorly localized and diffuse, and 5) is accompanied by autonomic reflexes. 49 Intense visceral pain may be associated with autonomic responses such as sweating or nausea or vomiting. With 208 Chapter 12 Ch12.qxd 4/6/2005 4:27 PM Page 208 inflammation, visceral nociceptors, unlike somatic, can be sensitized to non-noxious stimuli pain. This may cause heightened pain or exaggerated pain responses during diag- nostic procedures that manipulate or stretch inflamed tissues. Interventional techniques described later may be extremely helpful in controlling visceral pains. N EUROPATHIC P AIN Neuropathic pain is the most complex and challenging to treat. It results from direct injury to peripheral nerves or central nervous system and can also occur from a disrup- tion in the central processing of pain caused by peripheral nerve injury (central pain). The primary mechanisms for neuropathic pain do not involve direct activation of noci- ceptors—hence it is often referred to as non-nociceptive mediated pain. Clinically, neu- ropathic pain syndromes appear to be less responsive to opioid analgesics than somatic and visceral pain. As a result, patients will often require higher doses of opioid analgesics and may still not achieve acceptable pain relief. Opioid therapy can be slowly titrated up to the point that patients get relief or experience intolerable toxicities (eg, sedation, nau- sea). Selection of opioid analgesics is critical, and nonopioid combinations should be avoided so that doses can be escalated without added toxicities and ceiling effects. Greater benefits may be derived from combining opioid analgesics with effective adju- vant agents such as tricyclic antidepressants and anticonvusants that have documented efficacy in the treatment of neuropathic pain. Selective interventional techniques includ- ing temporary nerve blocks, neurolysis or nerve destruction procedures, and neuraxial (epidural or subarachnoid) therapy have demonstrated significant benefits. P RINCIPLES OF C HRONIC O PIOID A NALGESIC T HERAPY Chronic opioid analgesic therapy is indicated for mild to severe pain that has not responded to nonopioid preparations. Centrally acting opioid-agonists (eg, codeine, fen- tanyl, hydrocodone, oxycodone, morphine, hydromorphone) have an affinity for mu receptors and are preferred over other opioid preparations. Opioids such as meperidine (Demerol, Sanofi-Synthelabo, New York, NY) and proproxyphene (active agent in Darvocet, Eli Lilly & Co, Indianapolis, In) are weak and have toxic metabolites that accumulate with repeated dosing, and therefore should not be used for the management of chronic cancer pain. The toxic metabolite of meperidine (normeperidine) can lead to seizures; and cardiac toxicity may occur from the metabolite of proproxyphene. Even with its serious limitations, proproxphene is over prescribed; it is no better in its anal- gesic efficacy than acetaminophen or aspirin. The NCCN has recommendations for opi- oid prescribing, titration, and maintenance, as well as oral and parenteral dose equiva- lents. Guidelines for Chronic Opioid Therapy For mild to moderate pain: Begin with less potent, regularly scheduled short-acting opioids such as combination opioid products. These include codeine + acetaminophen (Tylenol #3, #4 [McNeill PPC, Milltown, NJ]), hydrocodone + acetaminophen (Vicodin, [Abbott Labs, Abbott Park, Ill]), and oxycodone + acetaminophen (Percocet, [Novartis, Cambridge, Mass]). Use caution to avoid doses of combination products con- taining acetaminophen that exceed the maximum daily dose of 4000 mg, especially in older persons. For moderate to severe pain: Initiate therapy with regularly scheduled more potent short-acting opioids such as oxycodone (Oxy IR, OxyFast [Purdue, Stamford, Conn]), morphine (MSIR [Purdue]) or hydromorphone (Dilaudid [Abbott]). The Assessment and Management of Acute and Chronic 209 Ch12.qxd 4/6/2005 4:27 PM Page 209 F OR THE E LDERLY Start low and go slow. Be aware of analgesic peak effects and duration. A trial of short-acting opioids at half the usual starting dose for adults should be initiated. Peak effects from the opioid may be heightened in the elderly and duration extended. Initial prescribing should allow for longer dosing intervals until the response to therapy can be evaluated. In addition, avoid initial therapy with opioids having an extended T½ (half- life) (eg, methadone) or long-acting opioid preparations in older persons who are opi- oid-naive. F OR L ONG -T ERM P AIN C ONTROL Consider long-acting opioids when the response to shorter-acting agents can be eval- uated and controlled-released morphine (MSContin [Purdue]), oxycodone (OxyContin [Purdue]), or transdermal fentanyl system (Duragesic [Abbott]). The transdermal fen- tanyl patch, which provides a convenient application every 72 hours, should be consid- ered for patients who are not able to take oral medication or absorb it (eg, chronic nau- sea or intermittent vomiting, noncompliance with opioid use, or mechanical GI obstruction). Titration may be difficult with severe progressive pain and therefore, ade- quate rescue medication should be available until steady state levels are reached. The lowest available patch strength, 25 mcg/hour, should not be applied to opioid-naive patients. R ESCUE OR S UPPLEMENTAL M EDICATION Supplemental analgesia with short-acting opioid agents can prevent and minimize intermittent painful episodes; however, rescue opioid medication is most effective if ade- quate doses are taken in anticipation of exacerbations of pain. Transmucosal fentanyl cit- rate (OTCF) (Actiq [Cephalon, West Chester, Pa]) can provide pain relief within 5 min- utes. 8,50 Generally, intermittent rescue doses of oral opioids should be approximately 10 to 30% of the daily oral opioid requirement of regularly scheduled continuous opioid analgesia. R ESPONSE TO T HERAPY Subjective pain rating scales and a pain relief scale can be used to evaluate response to opioid therapy. Clinically, other parameters such as improved function, mood, and appetite may also be indicators of decreased pain. C ONCURRENT U SE OF O THER P SYCHOACTIVE D RUGS The concurrent use of other psychoactive drugs, particularly if initiated with opioids or close to the time of starting therapy with opioids, obscures assessment of the unto- ward effects of opioids. If adjuvant agents for pain must be initiated, it is best to intro- duce agents singly and allow ample time (at least several days before giving a new agent with potential psychoactive effects. O PIOID -R ELATED S IDE E FFECTS A major side effect of opioids is constipation. Mild laxatives such as milk of magne- sia, senna preparations (Senokot [Purdue]), casanthranol and docusate (Pericolace [Purdue]), lactulose, or bisacodyl (Dulcolax [Boehringer Ingelheim, Germany]) should be started when opioids are intiated. Stool softeners alone do little or nothing to allevi- ate opioid-induced constipation. Unlike many other adverse effects from opioids, patients do not develop tolerance to the effects of opioids on the bowel, therefore, con- tinued use of laxatives is necessary as long as opioid therapy is maintained. 210 Chapter 12 Ch12.qxd 4/6/2005 4:27 PM Page 210 INTERVENTIONAL TECHNIQUES When optimal oral pharmacological therapy is ineffective or leads to unacceptable side effects, interventional pain management techniques should be considered. The WHO Analgesic Step Ladder for cancer pain management outlines several sequential strategies for alleviating persistent and uncontrolled pain with Step 4, the highest level, encompassing invasive procedures (Figure 12-3). Several interventional approaches such as parenteral opioid infusions, neuraxial medication infusion, neurolytic blockade, and other procedures (eg, vertebroplasty) offer effective alternatives to pain management. Substantial progress has been made over the past two decades in elucidating appropriate selection criteria and refining technology for these invasive techniques. Moreover, advances in the radiological diagnostics have provided significant advantages in precise placement of neuraxial (intraspinal) catheters and safety with the delivery of neuroabla- tive agents (ie, phenol and alcohol). The NCCN recommendations for procedural strategies are outlined in Figures 12-4. PARENTERAL OPIOD INFUSIONS C ONTINUOUS I NTRAVENOUS I NFUSION OF O PIOIDS Parenteral opioid administration is indicated in patients who experience intolerance to oral administration because of GI obstruction, malabsorption, opioid-induced nau- sea/vomiting, dysphagia, or high opioid requirements necessitate large number of pills or applications of transdermal systems. Patients with severe episodic pain with move- ment or unpredictable spontaneous pain may benefit from self-administered demand dose or a patient-controlled analgesia (PCA) feature in addition to a continuous intra- venous infusion (CII). Calculations for PCA demand doses are determined based on the hourly continuous infusion. The bolus dose should be 50 to 100% of the continuous The Assessment and Management of Acute and Chronic 211 Figure 12-3. Modified WHO Analgesic Step Ladder for- cancer pain management to include a fourth step of inter- ventional pain management modalities. (Adapted from Miguel R. Cancer Control. 2000;7:149-156.) Ch12.qxd 4/6/2005 4:27 PM Page 211 212 Chapter 12 Figure 12-4A. NCCN cancer pain guidelines. (Adapted and reproduced with permission from the NCCN 1.2004 Cancer Pain Guideline, The Complete Library of NCCN Clinical Prac- tice Guidelines in Oncology [CD-ROM]. Jenkintown, Pennsylvania: ©National Comp- rehensive Cancer Network, December 2004. To view the most recent and complete ver- sion of the guideline, go online to www.nccn.org.) NCCN Practice Guidelines in Oncology—v.1.2004 CANCER PAIN 1 High benefits/risk ratio examples: celiac plexus, superior hypogastric plexus, and peripheral nerves Ch12.qxd 4/6/2005 4:27 PM Page 212 The Assessment and Management of Acute and Chronic 213 1 Neuraxial encompasses both the epidural ase well as intrathecal routes. NCCN Practice Guidelines in Oncology—v.1.2004 CANCER PAIN Figure 12-4B. NCCN cancer pain guidelines (continued). (Adapted and reproduced with permission from the NCCN 1.2004 Cancer Pain Guideline, The Complete Library of NCCN Clinical Practice Guidelines in Oncology [CD-ROM]. Jenk- intown, Pennsylvania: ©Nat- ional Comprehensive Cancer Network, December 2004. To view the most recent and complete version of the guideline, go online to www.nccn.org.) Ch12.qxd 4/6/2005 4:27 PM Page 213 infusion dose and the interval for patient access may vary from every 15 to 60 minutes. PCA allows patients to gain rapid control over exacerbations of pain without the need for family and home health nurse interventions. PCA technology is only effective if patients have the cognitive and functional capabilities to self-administer medication. Doses are adjusted by taking into account pain intensity, demand dose requirements and disposition of the patient. If patients are not experiencing side effects from the opioid, escalations of about 10 to 25% of the hourly rate can be safely done every 24 hours for unrelieved pain. Continuous Subcutaneous Infusion of Opioids Continuous subcutaneous infusion of opioids (CSCI) is often considered for the same reasons as CII, but when it is not possible to insert an intravenous access line or when venous access is limited. Starting doses are calculated based on the conversion of the 24-hour oral/transdermal to an equianalgesic intravenous dose requirement, using an opioid conversion table and dividing this dose by 24 for an hourly rate. Tissue irrita- tion is minimized when volumes under 2 mL/hour are delivered by using the maximum concentration of the opioid. A patient-controlled demand dose feature can be pro- grammed into the drug delivery infusion device. Demand doses should not exceed 1 to 2 mL and availability of access with a lock-out interval should be every 30 to 60 min- utes. A 25- or 27-gauge butterfly needle is inserted subcutaneously anywhere with the most preferred sites including the infraclavicular fossa, chest wall, or abdomen for ease of ambulation. Absorption of subcutaneous opioids is rapid, and steady-state plasma lev- els are generally approached within an hour. Most parenteral opioids are suitable for CSCI, although morphine and hydromorphone are used most commonly. 51 NEURAXIAL (INTRASPINAL) ANALGESIA Neuraxial analgesia is achieved by the epidural or intrathecal administration of opi- oids alone or in combination with other agents such as local anesthetics (bupivacaine or ropivacaine) or clonidine, an alpha-2 agonist effective for the treatment of neuropathic pain. This modality is useful in basically two groups of patients: those with intolerable opioid related side-effects or pain unrelieved in spite of escalating doses of opioids and adjuvant agents. Neuraxial opioid therapy is accomplished by introducing minute quan- tities of opioids in close proximity to their receptors (substantia gelatinosa of the spinal cord) achieving high local concentrations. With this therapy, analgesia may be superior to what is achieved when opioids are administered systemically by other routes, and since the absolute amount of drug administered is reduced, side effects are minimized. In addition to opioids, local anesthetics and other coanalgesic medications can enhance the analgesic effect. The neuraxis can be accessed via an intrathecal, epidural, or intra- ventricular approach. For more long-term therapy, greater than three months, intrathe- cal administration with an implantable device or epidural therapy with a tunneled exter- nalized catheter or implantable port are preferred to avoid potential infection. The most important aspect of this therapy is its reversibility and the reliability and simplicity of advanced screening measures to confirm effectiveness. Screening is gener- ally accomplished on an outpatient basis by observing the patient’s response either to a morphine infusion via a temporary percutaneous epidural catheter or a single intrathe- cal injection. If improved pain control and reduced side effects are sufficiently com- pelling to warrant more prolonged therapy, then a temporary catheter for period of days to weeks is placed or a permanent implanted catheter along with medication reservoir 214 Chapter 12 Ch12.qxd 4/6/2005 4:27 PM Page 214 infusion device is surgical implanted. 52 The MD Anderson Cancer Center decision- making algorithm is shown in Figure 12-5. A recently published multi-center prospec- tive randomized clinical trial by Smith et al compared intrathecal therapy to continued medical management, revealing a trend toward better analgesia in the intrathecal group with improved side effect profile and increased survival in the intrathecal group. 53 Neuraxial analgesia is suitable for patients at any stage of their disease, including those who are considered free of disease, but who are plagued with persistent unrelieved pain. This technique is contraindicated in patients with systemic or localized infections or those with any form of a coagulopathy. NERVE BLOCKS Cancer patients are often referred to pain management specialists for a “quick cure” or because systemic analgesics seem to be ineffective. Many referring physicians are under the mistaken impression that “nerve blocks” alleviate all types of pain. Some focal pain syndromes are amenable to these procedures, as outlined below, but many are not. Generally, the more focal the pain, the easier it is to locally block sensory nerves involved in pain transmission. Unfortunately, peripheral sensory blocks also cause motor impair- The Assessment and Management of Acute and Chronic 215 Figure 12-5. Decision-making algorithm for the use of neuraxial analgesia in treating can- cer pain. (Adapted from Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathe- cal analgesia is effective in treating refractory cancer pain. Pain Medicine, 5(3);239-247, 2004.) Epidural catheter (Tunneled, Du Pens, or epidural portacath) Intrathecal catheter (Tunneled, Du Pens, or epidural portacath) IT Catheter Trial Implant Pump Further Medical Management • Failed opiod rotation (including methadone) • Failed optimizing breakthrough medications • Failed maximizing adjuvants (see text for details) Refractory Cancer Pain** Life Expectancy <3 months Life Expectancy >3 months Single Shot IT Trial • Need for focal local anesthetics (eg, chest wall mass) • Anticipated need for high dose local anesthetics • Diffuse pain, epidural space obliterated by tumor or surgery • Need for IT-PCA or unavailability of programming for implanted pump • Somatic or Visceral Pain • Neuropathic Pain • Severe incidental pain • Equivocal Result • >50% Pain Relief • <50% Pain Relief ** Ch12.qxd 4/6/2005 4:27 PM Page 215 [...]... 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