Nathan I. Cherny

The management of cancer pain.

Any therapeutic strategy developed for patients experiencing cancer pain depends on the goals of care, which can be broadly categorized as prolonging survival, optimizing comfort, and optimizing function. The relative priority of these goals for any individual should direct therapeutic decision‐making.

[Drug therapy for tumor pain I. Properties of non-opioids and opioids.].

Analgesic pharmacotherapy represents one of the major approaches to the treatment of cancer pain, since it is used in almost every patient. A thorough evaluation of the physical and mental status of the patient and of the pain is as necessary as a sound understanding of the pharmacokinetic and pharmacodynamic characteristics of the analgesics selected. The World Health Organization (WHO) has issued a basic 3 stage progression for the treatment of cancer pain, the “WHO Analgesic Ladder”. Assignment to the stages depends mainly on the intensity of the pain rather than on its specific aetiology. Mild to moderate pain is treated with non-opioid drugs; moderate to severe pain, with a combination of a “weak” opioid and a non-opioid; and “strong” opioids should be used in combination with a non-opioid in the case of severe pain. Adjuvant drugs can be added if specifically indicated. Nonopioid analgesics include non-acidic compounds, e. g. paracetamol and metamizole, and acidic non-opioids, e. g. acetylsalicylic acid and newer non-steroidal anti-inflammatory drugs (NSAID). In contrast to most of the opioid analgesics, they have a ceiling effect for analgesia. Addiction and tolerance are extremely rare concerns. Opioids can be subgrouped into “weak” (e. g., codeine, dextropropoxyphene) and “strong” opioids (e. g., morphine) and also into drugs interacting with different opioid-receptor subtypes. Whereas pure agonists (e. g., morphine) produce increasingly intense analgesia with increasing dose, partial agonists and agonist-antagonists have a ceiling effect for analgesia and therefore have only a minor role in the treatment of chronic pain in cancer patients. Adverse effects occur in most patients in a dose-dependent manner. The most common of these is constipation; nausea, vomiting and sedation occur mostly at the start and can usually be treated effectively. The appropriate dosage, route of administration and dosage scheme of analgesics needs to be worked out for each individual patient in intensive work with the patient and a close follow-up, for years if necessary. Some analgesics may not be available in some countries, or only in specific preparations.ZusammenfassungDer Einsatz von Analgetika bei der Behandlung von Tumorschmerzen stellt einen wichtigen Therapieansatz dar, der bei fast allen Patienten mit einem Tumorleiden Anwendung findet. Die Weltgesundheitsorganisation (WHO) hat Empfehlungen zum Einsatz von Analgetika bei Tumorschmerzen herausgegeben, in denen 3 Stufen unterschieden werden. Die jeweilige Auswahl der Analgetika orientiert sich hierbei primär an der Intensität der Schmerzen; geringe bis mittelstarke Schmerzen, mittelstarke bis starke Schmerzen und starke Schmerzen. Hauptvertreter analgetischer Substanzen für diese 3 Stufen sind: Acetylsalicylsäure, Codein und Morphin. Nichtopioide und Opioide können miteinander kombiniert und bei gegebener Indikation durch adjuvante Medikamente ergänzt werden. Neben einer genauen Befunderhebung und Schmerzanamnese ist für eine suffiziente Schmerztherapie die Kenntnis pharmakokinetischer und pharmakodynamischer Eigenschaften der Substanzen notwendig. Länderspezifisch können verschiedene Stoffe nicht oder nur in bestimmten Präparationen zugelassen sein. Die angegebenen Dosierungen sind nur Anhaltspunkte für die Therapie, die für jeden Patienten individuell und unter Abwägung von erreichter Schmerzreduktion und dem gleichzeitigen Auftreten von Nebenwirkungen gestaltet werden muß.Analgesic pharmacotherapy represents one of the major approaches to the treatment of cancer pain, since it is used in almost every patient. A thorough evaluation of the physical and mental status of the patient and of the pain is as necessary as a sound understanding of the pharmacokinetic and pharmacodynamic characteristics of the analgesics selected. The World Health Organization (WHO) has issued a basic 3 stage progression for the treatment of cancer pain, the WHO Analgesic Ladder. Assignment to the stages depends mainly on the intensity of the pain rather than on its specific aetiology. Mild to moderate pain is treated with non-opioid drugs; moderate to severe pain, with a combination of a weak opioid and a non-opioid; and strong opioids should be used in combination with a non-opioid in the case of severe pain. Adjuvant drugs can be added if specifically indicated. Nonopioid analgesics include non-acidic compounds, e. g. paracetamol and metamizole, and acidic non-opioids, e. g. acetylsalicylic acid and newer non-steroidal anti-inflammatory drugs (NSAID). In contrast to most of the opioid analgesics, they have a ceiling effect for analgesia. Addiction and tolerance are extremely rare concerns. Opioids can be subgrouped into weak (e. g., codeine, dextropropoxyphene) and strong opioids (e. g., morphine) and also into drugs interacting with different opioid-receptor subtypes. Whereas pure agonists (e. g., morphine) produce increasingly intense analgesia with increasing dose, partial agonists and agonist-antagonists have a ceiling effect for analgesia and therefore have only a minor role in the treatment of chronic pain in cancer patients. Adverse effects occur in most patients in a dose-dependent manner. The most common of these is constipation; nausea, vomiting and sedation occur mostly at the start and can usually be treated effectively. The appropriate dosage, route of administration and dosage scheme of analgesics needs to be worked out for each individual patient in intensive work with the patient and a close follow-up, for years if necessary. Some analgesics may not be available in some countries, or only in specific preparations.

[Pharmacotherapy of cancer pain : 2. Use of opioids.].

The adequate use of opioids in the treatment of chronic cancer pain requires sound knowledge of selection criteria for the various opioids, the routes of administration, dosages, dosing schemes and possible side effects. Drug selection depends on the intensity of pain rather than on the specific pathophysiology. Mild to moderate pain can often be treated effectively by so-called weak opioids. These include codeine, dihydrocodeine and dextropropoxyphene. Non-opioid analgesics, like acetylsalicylic acid or paracetamol can be added according to the analgesic ladder proposed by the World Health Organization (WHO). If adequate pain relief is not achieved strong opioids are required. The route of administration that is the safest and the least invasive for the patient should be chosen. Non-invasive (oral, rectal, sublingual, transdermal and intranasal) and invasive routes (intravenous, subcutaneous, spinal and epidural) are available (Table 8). Noninvasive routes are preferred, and most patients can be maintained on oral opioids. Alternatively, in some patients pain can be managed by the sublingual (buprenorphine) route. A transdermal preparation exists for fentanyl, but has not yet been approved for the German market. If the oral route cannot be used or if large doses are required, it will be necessary to change to an invasive route. Intravenous bolus injections provide the fastest onset of analgesic action. They are mostly used in very severe pain. Repeated injections can be avoided by using intravenous or subcutaneous infusions. Various types of pumps delivering analgesics at constant basal infusion rates with the option of rescue doses in case of breakthrough pain are available (patient-controlled analgesia=PCA). Opioids frequently used for s. c. infusion are morphine and hydromorphone. Adjuvant drugs (antiemetics, anxiolytics) can be added. Epidural or intrathecal administration of opioids should only be used in intractable pain or if severe side effects, such as sedation and confusion, will arise with systemic opioids. Morphine, hydromorphone, fentanyl and sufentanil have been used, as have other additional compounds (e.g. local anaesthetics, clonidine). Intracerebroventricular application of morphine has been used only occasionally. In all cases, opioids should be given on to a fixed time schedule thereby, preventing pain from recurring. Additional rescue doses (approximately 50% of baseline single dose) are given for break-through pain. The most frequent side effect of opioids is constipation, and the administration of laxatives is often recommended (Table 5). Nausea, vomiting, sedation and confusion mostly occur in the beginning of opioid therapy. In contrast to constipation, tolerance to these effects develops within days or weeks. True dependence or psychological addiction rarely occurs in patients with chronic cancer pain. In most cases, progression of the underlying disease associated with increasing tissue damage and increasing pain is found. Fear of dependence and addiction often contributes to undertreatment of patients suffering from chronic cancer pain.The adequate use of opioids in the treatment of chronic cancer pain requires sound knowledge of selection criteria for the various opioids, the routes of administration, dosages, dosing schemes and possible side effects. Drug selection depends on the intensity of pain rather than on the specific pathophysiology. Mild to moderate pain can often be treated effectively by so-called “weak” opioids. These include codeine, dihydrocodeine and dextropropoxyphene. Non-opioid analgesics, like acetylsalicylic acid or paracetamol can be added according to the “analgesic ladder” proposed by the World Health Organization (WHO). If adequate pain relief is not achieved “strong” opioids are required. The route of administration that is the safest and the least invasive for the patient should be chosen. Non-invasive (oral, rectal, sublingual, transdermal and intranasal) and invasive routes (intravenous, subcutaneous, spinal and epidural) are available (Table 8). Noninvasive routes are preferred, and most patients can be maintained on oral opioids. Alternatively, in some patients pain can be managed by the sublingual (buprenorphine) route. A transdermal preparation exists for fentanyl, but has not yet been approved for the German market. If the oral route cannot be used or if large doses are required, it will be necessary to change to an invasive route. Intravenous bolus injections provide the fastest onset of analgesic action. They are mostly used in very severe pain. Repeated injections can be avoided by using intravenous or subcutaneous infusions. Various types of pumps delivering analgesics at constant basal infusion rates with the option of rescue doses in case of breakthrough pain are available (patient-controlled analgesia=PCA). Opioids frequently used for s. c. infusion are morphine and hydromorphone. Adjuvant drugs (antiemetics, anxiolytics) can be added. Epidural or intrathecal administration of opioids should only be used in intractable pain or if severe side effects, such as sedation and confusion, will arise with systemic opioids. Morphine, hydromorphone, fentanyl and sufentanil have been used, as have other additional compounds (e.g. local anaesthetics, clonidine). Intracerebroventricular application of morphine has been used only occasionally. In all cases, opioids should be given on to a fixed time schedule thereby, preventing pain from recurring. Additional rescue doses (approximately 50% of baseline single dose) are given for break-through pain. The most frequent side effect of opioids is constipation, and the administration of laxatives is often recommended (Table 5). Nausea, vomiting, sedation and confusion mostly occur in the beginning of opioid therapy. In contrast to constipation, tolerance to these effects develops within days or weeks. True dependence or psychological addiction rarely occurs in patients with chronic cancer pain. In most cases, progression of the underlying disease associated with increasing tissue damage and increasing pain is found. Fear of dependence and addiction often contributes to undertreatment of patients suffering from chronic cancer pain.ZusammenfassungVoraussetzungen für den Einsatz von Opioiden bei der Therapie von Tumorschmerzen sind Kenntnisse über die Auswahl der Medikamente, die möglichen Applikationsformen und ihre Dosierung sowie Nebenwirkungen einer Opioidtherapie. Die Schmerzstärke stellt das wichtigste Kriterium zur Auswahl des Opioids dar. Geringe bis mittelstarke Schmerzen können meist ausreichend mit schwach wirksamen Opioiden (Dihydrocodein, Dextropropoxyphen) in Kombination mit einem Nichtopioid-Analgetikum (ASS) behandelt werden. Veränderungen der Pharmakokinetik und Pharmakodynamik von Opioiden durch erhöhtes Alter der Patienten, Leber-oder Niereninsuffizienz sowie Interaktionen mit anderen Medikamenten müssen berücksichtigt werden. Bei diesen Erkrankungen sollten Präparate mit kurzen Plasmahalbwertszeiten verwendet werden. Die Einnahme des Opioids soll für die Patienten so einfach wie möglich sein und eine suffiziente Schmerzreduktion bewirken. Nichtinvasive Applikationsformen (z.B. oral, rektal, sublingual, transdermal) und invasive Formen (intravenös, subkutan) sind möglich. Nichtinvasive Applikationsformen sind zu bevorzugen, und insbesondere orale Medikationen werden von den Patienten gut toleriert. Durch Verwendung von Retardpräparaten kann die Anzahl der täglichen Medikamenteneinnahmen verringert werden. Die Opioide sollten regelmäßig (zu bestimmten Zeiten) eingenommen werden und beim Auftreten von Schmerzspitzen durch zusätzliche Opioidgaben (ca. 50% der jeweiligen Einzeldosis) ergänzt werden. Ist eine orale Medikation nicht durchführbar oder sind größere Opioiddosen notwendig, kann auf eine invasive Applikationsform gewechselt werden. Häufige Bolusinjektionen können durch die Verwendung kontinuierlicher Infusionen (i.v., s.c.) umgangen werden. Auch hier kann mittels Infusionspumpen das Prinzip einer Basisdosierung mit möglichen Zusatzdosen bei Schmerzspitzen realisiert werden (Patient Controlled Analgesia=PCA). Für die i.v. und s.c. Infusion werden meist Morphin und Hydromorphon verwendet, für die rückenmarksnahe Anwendung zusätzlich auch Fentanyl und Sufentanil. Die spinale Applikation kann bei Nebenwirkungen durch oral oder parenteral angewandte Opioide versucht werden. Die gleichzeitige Gabe von Koanalgetika (z.B. Clonidin) und Adjuvanzien (Antiemetika, Anxiolytika) ist möglich. Die intrazerebroventrikuläre Applikation von Opioiden ist nur sehr selten notwendig. Die häufigste Nebenwirkung einer Opioidtherapie ist Obstipation. Ihr Auftreten ist so wahrscheinlich, daß die prophylaktische Gabe von Laxanzien indiziert ist. Zu Beginn einer Opioidtherapie treten häufig Übelkeit, Erbrechen sowie Sedierung auf. Eine Toleranzentwicklung ist für diese Wirkungen innerhalb der ersten Tage bis Wochen zu beobachten-für die Obstipation gilt dies jedoch nicht. Eine psychische Abhängigkeit durch Opioide tritt bei Patienten mit chronischen Schmerzen nur extrem selten auf. Meist ist bei einer Erhöhung der Dosis ein Fortschreiten der Grunderkrankung nachzuweisen. Unsicherheit und fehlende Kenntnis dieser Phänomene bei Patienten und Ärzten führen nicht selten zu einer Unterversorgung chronisch schmerzkranker Patienten mit potenten Analgetika.

Pharmacotherapy of Cancer Pain

Chronic pain is experienced by approximately one-third of all cancer patients and as many as 70 to 90% of those with advanced disease.1 Although established pharmacotherapeutic strategies have been demonstrated to benefit most patients, undertreatment remains common.1 This unacceptable situation must be remedied; relief of cancer pain is an ethical imperative and it is incumbent upon clinicians to maximize the knowledge, skill, and diligence needed to attend to this task.2Analgesic pharmacotherapy is the mainstay approach in the management of cancer pain.3,4 Optimal therapy depends on an understanding of the clinical pharmacology of analgesic drugs and comprehensive assessment of the pain, medical condition, and psychosocial status of the patient. Through a process of repeated evaluations, therapy with opioid, nonopioid, and adjuvant analgesics is individualized to achieve and maintain a favorable balance between pain relief and adverse effects.An expert committee convened by the Cancer Unit of the World Health Organization has proposed a useful approach to drug selection for cancer pain, which has become known as the analgesic ladder (Fig. 1).3 When combined with appropriate dosing guidelines, this approach is capable of providing adequate relief to 70 to 90% of patients.5-9 Emphasizing that the intensity of pain, rather than its specific etiology, should be the prime consideration in analgesic selection, the approach advocates the following three basic steps:Step 1. Patients with mild to moderate cancer-related pain should be treated with a nonopioid analgesic, which should be combined with an adjuvant analgesic if a specific indication for one exists.Step 2. Patients who are relatively nontolerant and present with moderate to severe pain, or who tail to achieve adequate relief after a trial of a nonopioid analgesic, should be treated with a socalled weak opioid; this drug is typically combined with a nonopioid and may be coadministered with an adjuvant analgesic or other adjuvant drug, if there is an indication for one.Step 3. Patients who present with severe pain, or fail to achieve adequate relief following appropriate administration of drugs on the second rung of the analgesic ladder, should receive a so-called strong opioid, which may be combined with a nonopioid analgesic or an adjuvant drug as indicated.

Pharmacotherapy of cancer pain. 3. Adjuvant drugs.

Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100-150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10-15 mg/d, increasing to 30-90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60-120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100–150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10–15 mg/d, increasing to 30–90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60–120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.ZusammenfassungAdjuvanzien zur Schmerztherapie sind Substanzen, die keine primären Analgetika sind, aber bei bestimmten Erkrankungen oder Schmerzen eine analgetische Wirkung entfalten können. Sie können gemeinsam mit anderen Analgetika auf jeder Stufe der analgetischen Stufentherapie eingesetzt werden. Adjuvanzien können unterteilt werden in solche zum Einsatz bei neuropathischen Dauerschmerzen, neuropathischen einschießenden Schmerzen, sympathisch unterhaltenen Schmerzen, Knochenschmerzen und solche mit vielfältigen Einsatzmöglichkeiten. Bei neuropathischen Dauerschmerzen, die schlecht auf Opioide ansprechen, werden vielfach Antidepressiva verwendet. Trizyklische Verbindungen vom Amitriptylin-Typ sind aufgrund der Erfahrung zu bevorzugen. Analgetische Effekte treten meist vor Veränderungen der Stimmungslage auf. Der membranstabilisierende Effekt von Lokalanästhetika kann ebenfalls ausgenutzt werden. Mit Ausnahme von Mexiletin sind jedoch die Nebenwirkungen recht stark ausgeprägt. Lokalanästhetika sollten daher keine Standardtherapie sein. Weiterhin können Therapieversuche mit systemischen oder rückenmarksnahen Gaben von Clonidin und der topischen Applikation von Capsaicin unternommen werden. Neuropathische Schmerzen mit einschießendem Charakter sprechen gut auf Antikonvulsiva an. Carbamazepin ist das hierfür am besten untersuchte Medikament. Clonazepam, Phenytoin und Valproat sind Medikamente der zweiten Wahl. Einschleichende Dosierungen, Kontrollen der Plasmakonzentrationen und des Blutbildes sind bei diesen Medikamenten notwendig. Neben Antikonvulsiva wird für einschießende Schmerzen auch Baclofen verwendet. Sympathisch unterhaltene Schmerzen sind von bestimmten Charakteristika geprägt und treten bei einer Vielzahl recht ähnlicher Krankheitsbilder z. B. der sympathischen Reflexdystrophie (SRD), aber auch bei Tumorpatienten auf. Sind Sympathikusblockaden nicht erfolgreich, können Sympatholytika versucht werden. Phenoxybenzamin und Prazosin sind bei Kausalgie schmerzlindernd, sollten jedoch wegen der blutdrucksenkenden Wirkung vorsichtig verwendet werden. Eine Wirksamkeit von Nifidepin bei SRD ist ebenfalls beschrieben. Knochenschmerzen treten bei Tumorpatienten häufig auf. Nichtsteroidale Antiphlogistika und Steroide zeigen oft eine gute Wirkung. Biphosphonate sind bei ossären Metastasen wirksam. Radioisotope und Calcitonin haben ebenfalls einen analgetischen Effekt, ihr Einsatz bei Knochenschmerzen bei Tumorpatienten wird aber unterschiedlich beurteilt.

Medikamentöse Therapie von Tumorschmerzen@@@Pharmacotherapy of cancer pain: II. Anwendung von Opioiden@@@2. Use of opioids

The adequate use of opioids in the treatment of chronic cancer pain requires sound knowledge of selection criteria for the various opioids, the routes of administration, dosages, dosing schemes and possible side effects. Drug selection depends on the intensity of pain rather than on the specific pathophysiology. Mild to moderate pain can often be treated effectively by so-called weak opioids. These include codeine, dihydrocodeine and dextropropoxyphene. Non-opioid analgesics, like acetylsalicylic acid or paracetamol can be added according to the analgesic ladder proposed by the World Health Organization (WHO). If adequate pain relief is not achieved strong opioids are required. The route of administration that is the safest and the least invasive for the patient should be chosen. Non-invasive (oral, rectal, sublingual, transdermal and intranasal) and invasive routes (intravenous, subcutaneous, spinal and epidural) are available (Table 8). Noninvasive routes are preferred, and most patients can be maintained on oral opioids. Alternatively, in some patients pain can be managed by the sublingual (buprenorphine) route. A transdermal preparation exists for fentanyl, but has not yet been approved for the German market. If the oral route cannot be used or if large doses are required, it will be necessary to change to an invasive route. Intravenous bolus injections provide the fastest onset of analgesic action. They are mostly used in very severe pain. Repeated injections can be avoided by using intravenous or subcutaneous infusions. Various types of pumps delivering analgesics at constant basal infusion rates with the option of rescue doses in case of breakthrough pain are available (patient-controlled analgesia=PCA). Opioids frequently used for s. c. infusion are morphine and hydromorphone. Adjuvant drugs (antiemetics, anxiolytics) can be added. Epidural or intrathecal administration of opioids should only be used in intractable pain or if severe side effects, such as sedation and confusion, will arise with systemic opioids. Morphine, hydromorphone, fentanyl and sufentanil have been used, as have other additional compounds (e.g. local anaesthetics, clonidine). Intracerebroventricular application of morphine has been used only occasionally. In all cases, opioids should be given on to a fixed time schedule thereby, preventing pain from recurring. Additional rescue doses (approximately 50% of baseline single dose) are given for break-through pain. The most frequent side effect of opioids is constipation, and the administration of laxatives is often recommended (Table 5). Nausea, vomiting, sedation and confusion mostly occur in the beginning of opioid therapy. In contrast to constipation, tolerance to these effects develops within days or weeks. True dependence or psychological addiction rarely occurs in patients with chronic cancer pain. In most cases, progression of the underlying disease associated with increasing tissue damage and increasing pain is found. Fear of dependence and addiction often contributes to undertreatment of patients suffering from chronic cancer pain.The adequate use of opioids in the treatment of chronic cancer pain requires sound knowledge of selection criteria for the various opioids, the routes of administration, dosages, dosing schemes and possible side effects. Drug selection depends on the intensity of pain rather than on the specific pathophysiology. Mild to moderate pain can often be treated effectively by so-called “weak” opioids. These include codeine, dihydrocodeine and dextropropoxyphene. Non-opioid analgesics, like acetylsalicylic acid or paracetamol can be added according to the “analgesic ladder” proposed by the World Health Organization (WHO). If adequate pain relief is not achieved “strong” opioids are required. The route of administration that is the safest and the least invasive for the patient should be chosen. Non-invasive (oral, rectal, sublingual, transdermal and intranasal) and invasive routes (intravenous, subcutaneous, spinal and epidural) are available (Table 8). Noninvasive routes are preferred, and most patients can be maintained on oral opioids. Alternatively, in some patients pain can be managed by the sublingual (buprenorphine) route. A transdermal preparation exists for fentanyl, but has not yet been approved for the German market. If the oral route cannot be used or if large doses are required, it will be necessary to change to an invasive route. Intravenous bolus injections provide the fastest onset of analgesic action. They are mostly used in very severe pain. Repeated injections can be avoided by using intravenous or subcutaneous infusions. Various types of pumps delivering analgesics at constant basal infusion rates with the option of rescue doses in case of breakthrough pain are available (patient-controlled analgesia=PCA). Opioids frequently used for s. c. infusion are morphine and hydromorphone. Adjuvant drugs (antiemetics, anxiolytics) can be added. Epidural or intrathecal administration of opioids should only be used in intractable pain or if severe side effects, such as sedation and confusion, will arise with systemic opioids. Morphine, hydromorphone, fentanyl and sufentanil have been used, as have other additional compounds (e.g. local anaesthetics, clonidine). Intracerebroventricular application of morphine has been used only occasionally. In all cases, opioids should be given on to a fixed time schedule thereby, preventing pain from recurring. Additional rescue doses (approximately 50% of baseline single dose) are given for break-through pain. The most frequent side effect of opioids is constipation, and the administration of laxatives is often recommended (Table 5). Nausea, vomiting, sedation and confusion mostly occur in the beginning of opioid therapy. In contrast to constipation, tolerance to these effects develops within days or weeks. True dependence or psychological addiction rarely occurs in patients with chronic cancer pain. In most cases, progression of the underlying disease associated with increasing tissue damage and increasing pain is found. Fear of dependence and addiction often contributes to undertreatment of patients suffering from chronic cancer pain.ZusammenfassungVoraussetzungen für den Einsatz von Opioiden bei der Therapie von Tumorschmerzen sind Kenntnisse über die Auswahl der Medikamente, die möglichen Applikationsformen und ihre Dosierung sowie Nebenwirkungen einer Opioidtherapie. Die Schmerzstärke stellt das wichtigste Kriterium zur Auswahl des Opioids dar. Geringe bis mittelstarke Schmerzen können meist ausreichend mit schwach wirksamen Opioiden (Dihydrocodein, Dextropropoxyphen) in Kombination mit einem Nichtopioid-Analgetikum (ASS) behandelt werden. Veränderungen der Pharmakokinetik und Pharmakodynamik von Opioiden durch erhöhtes Alter der Patienten, Leber-oder Niereninsuffizienz sowie Interaktionen mit anderen Medikamenten müssen berücksichtigt werden. Bei diesen Erkrankungen sollten Präparate mit kurzen Plasmahalbwertszeiten verwendet werden. Die Einnahme des Opioids soll für die Patienten so einfach wie möglich sein und eine suffiziente Schmerzreduktion bewirken. Nichtinvasive Applikationsformen (z.B. oral, rektal, sublingual, transdermal) und invasive Formen (intravenös, subkutan) sind möglich. Nichtinvasive Applikationsformen sind zu bevorzugen, und insbesondere orale Medikationen werden von den Patienten gut toleriert. Durch Verwendung von Retardpräparaten kann die Anzahl der täglichen Medikamenteneinnahmen verringert werden. Die Opioide sollten regelmäßig (zu bestimmten Zeiten) eingenommen werden und beim Auftreten von Schmerzspitzen durch zusätzliche Opioidgaben (ca. 50% der jeweiligen Einzeldosis) ergänzt werden. Ist eine orale Medikation nicht durchführbar oder sind größere Opioiddosen notwendig, kann auf eine invasive Applikationsform gewechselt werden. Häufige Bolusinjektionen können durch die Verwendung kontinuierlicher Infusionen (i.v., s.c.) umgangen werden. Auch hier kann mittels Infusionspumpen das Prinzip einer Basisdosierung mit möglichen Zusatzdosen bei Schmerzspitzen realisiert werden (Patient Controlled Analgesia=PCA). Für die i.v. und s.c. Infusion werden meist Morphin und Hydromorphon verwendet, für die rückenmarksnahe Anwendung zusätzlich auch Fentanyl und Sufentanil. Die spinale Applikation kann bei Nebenwirkungen durch oral oder parenteral angewandte Opioide versucht werden. Die gleichzeitige Gabe von Koanalgetika (z.B. Clonidin) und Adjuvanzien (Antiemetika, Anxiolytika) ist möglich. Die intrazerebroventrikuläre Applikation von Opioiden ist nur sehr selten notwendig. Die häufigste Nebenwirkung einer Opioidtherapie ist Obstipation. Ihr Auftreten ist so wahrscheinlich, daß die prophylaktische Gabe von Laxanzien indiziert ist. Zu Beginn einer Opioidtherapie treten häufig Übelkeit, Erbrechen sowie Sedierung auf. Eine Toleranzentwicklung ist für diese Wirkungen innerhalb der ersten Tage bis Wochen zu beobachten-für die Obstipation gilt dies jedoch nicht. Eine psychische Abhängigkeit durch Opioide tritt bei Patienten mit chronischen Schmerzen nur extrem selten auf. Meist ist bei einer Erhöhung der Dosis ein Fortschreiten der Grunderkrankung nachzuweisen. Unsicherheit und fehlende Kenntnis dieser Phänomene bei Patienten und Ärzten führen nicht selten zu einer Unterversorgung chronisch schmerzkranker Patienten mit potenten Analgetika.