Nociception, the perception of damage to or inflammation of tissue which is accompanied with the formation or release of chemical mediators that stimulate pain receptors, or so-called nociceptors. This primarily occurs no damage to nerve tissue. The nociceptors are nerve endings of afferent fibers. One speaks of nociceptive pain and differentiates somatic and visceral pain. Somatic pain is clearly
localized and has a sharp, dull, stabbing or throbbing character. Visceral pain is less localized and has a cramping or oppressive character. Usually responds nociceptive pain conventional analgesics. 6 7
Neurogenic pain, also known as neuropathic pain, arises in case of damage or dysfunction of the nervous system, both peripherally and centrally. 8 It arises after a latency period of days to months, persistent pain with extremely sensitive nociceptors. This usually has a burning, shooting or irritating character. Neurogenic pain is distinguished from nociceptive pain especially by abnormal pain sensations, such as excessive pain in response to a painful stimulus (hyperalgesia), or pain due to a stimulus that normally does not lead to pain (allodynia). This can occur even in a hypervariable region or anesthetic: hyperpathia. Neurogenic pain responds generally poorly to conventional analgesics and can be very difficult to treat. 9
Nociceptive chronic pain and pain ladder
Back upstairs
The general principles in the treatment of chronic malignant pain consist of: Preferably, for oral administration, the use of fixed doses in order to obtain continuous analgesia and the bijtitreren acts as breakthrough pain. The side effects should be discussed with the patient sedation, constipation and nausea / vomiting at the start of treatment. The therapy should be focused on the prevention of and not every time the treating pain.
Step 1: Non-opioids with or without adjuvant therapy
Step 2: opioids for moderate pain with funds from step 1
Step 3: opioids for moderate to severe pain with funds from step 1
Some experts recommend that in the treatment of pain or to skip step 2 of the ladder pain in the treatment of chronic malignant pain. One reason for not doing this is that it would have an emotional significance for many patients when they fairly quickly after step 1 'need to morphine. A recently published survey shows that Dutch doctors are relatively reluctant to prescribe morphine for pain. Doctors in Britain and the Scandinavian countries write three to eight times more morphine than their Dutch counterparts. 10 Opioids in patients with chronic malignant pain rarely addictive and 'opiofobie' is therefore no place. This 'opiofobie' may namely lead to undertreatment or setting too late to opioid therapy in patients with chronic malignant pain. 11-13 It is not known whether the same is also true for chronic benign pain.
The classic WHO ladder is increasingly also advocated for nociceptive chronic benign pain. In the remainder of this article will particularly examine the results of the clinical study with analgesics in this indication.
Paracetamol and NSAIDs (step 1 WHO)
Back upstairs
Paracetamol and NSAIDs have an analgesic and antipyretic effects. The NSAIDs, including acetylsalicylic acid, in addition, have an antiphlogistic effect. The term peripheral analgesics for this group of drugs is no longer used. One begins preferably with paracetamol and insufficient effect may be considered an NSAID.
Paracetamol
For patients with chronic malignant pain there is a maximum dose of 1g every 4 hours, 14 is usually a daily dose of from 3 to 4 g adequate. In practice, often paracetamol dose too low for fear of possible liver damage. In chronic pain can be applied doses to 6 g per day. With excessive alcohol consumption and intake of more than 6 g acetaminophen suddenly there is an absolute risk of liver damage. The bioavailability of rectally administered paracetamol is equal to that of the oral administration. However, the rate of absorption upon rectal administration, is less than for oral administration. This means that in case of chronic administration, similar doses of paracetamol given orally and rectally, are equally effective. In chronic benign pain is paracetamol first choice.
NSAIDs
There have been generating strong evidence that NSAIDs their peripheral analgesic effects partly via the central nervous system. That, NSAIDs central effects, was already known because of the central side effects, including headache (so-called. Analgesic headache), dizziness and tinnitus. 15
According to current views NSAIDs inhibit the enzyme cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The inhibition of COX-1 is potentially relevant to the (adverse) effects on the gastro-intestinal wall, the kidney flow, the vessels (hypertension), and the platelet aggregation. The inhibition of COX-2 is strongly related to the anti-inflammatory effect. This has led to the development of so-called COX-2-selective NSAIDs, which in the Netherlands meloxicam ( EB 1996; 30: 119-120 and 1997; 31: 38 ) and nabumetone Gebu 1994; 28: 48 ) are registered. In randomized controlled trials did not show that the newer NSAIDs have better efficacy than the more traditional means. A review article shows that in some studies but not in other studies not significantly fewer gastrointestinal side effects such as ulcers and erosions, of meloxicam have been demonstrated in patients with rheumatoid arthritis and coxarthrosis. 16 In these studies, however, non-equivalent dosages compared or was compared with agents that have a high risk of gastrointestinal side-effects, such as piroxicam. Meloxicam also can cause serious gastrointestinal events ( EB 1998; 32: 38 ). Of nabumetone has been shown in a few studies that it works just as effectively as ibuprofen, naproxen and diclofenac in the treatment of patients with rheumatoid arthritis or osteoarthritis. 17-19 Nabumetone would in these studies significantly fewer side effects on the gastric mucosa than other means. The structure of two of these studies, 17 18, however, leaves much to be desired, since there was compared with non-equivalent dosages of the conventional means. Meloxicam and nabumetone have fewer side effects, has not been shown in randomized double-blind study. A recent published cohort study ( EB 1998; 32: 63 and 100 ) are indications obtained which nabumetone, like ibuprofen, diclofenac, indomethacin and naproxen has the lowest risk of gastrointestinal side effects. 20 If NSAIDs are prescribed, the preference is for agents with the smallest risk of side effects, such as ibuprofen, diclofenac, or naproxen ( EB 1994; 28: 85-86 ) and possible nabumetone.
The clinical impression of experts in the treatment of pain is that NSAIDs have an added value in bone pain. A meta-analysis of the efficacy and safety However, it appears that an added value of classic NSAIDs has never been convincingly demonstrated by bone metastases. 21 from both the classical and the new resources not show any effect in controlled clinical trials in malignant pain, nor in non-malignant pain other than rheumatoid aandoeningen.2 Therefore, no statement can be made about the use of selective COX-2 inhibitors with pain that is not caused by rheumatoid arthritis. 22
In the treatment of chronic benign pain is the value of NSAIDs over acetaminophen, as regards the reduction of pain, not convincingly demonstrated. In a review of controlled clinical trials in the field of pharmacotherapy in gonarthrosis concluded that both NSAID and paracetamol is more effective than placebo. The effect of paracetamol is comparable to that of ibuprofen or naproxen. 23 Chronic use of NSAIDs should, especially given the risk of renal papillary necrosis and chronic renal failure are not recommended in patients older than 75 years, diuretics, liver cirrhosis or kidney disease. 24 25
NSAIDs in patients at risk
Two studies published in patients with joint disorders (particularly rheumatoid arthritis and osteoarthritis) requiring chronic NSAID and also had stomach ulcers or erosions in the stomach and / or duodenum, where the healing and protective effect of omeprazole compared with ranitidine and misoprostol. 26 27 Omeprazole cured the defects significantly better than ranitidine 26 and as effective as misoprostol. 27 Omeprazole protected significantly better than misoprostol. the authors have failed in both studies mentioned above indicate which type of NSAID used the patients. Furthermore, they have not been investigated or the prognosis, i.e., the side effects and the risk of recurrence, is dependent on the kind of NSAID that the patients used.
Local NSAIDs
In a recent meta-analysis of clinical trials in patients with acute and chronic pain as a result of a mono-arthritis or rheumatoid arthritis, bleaching topically applied NSAID's work to be significantly more effective than placebo. The local and systemic adverse events were similar to placebo. 28 However, the average observation period of the trials was only two weeks. Furthermore, no proper comparison could be made with oral NSAIDs, as the quality of those studies was too small. This complicates the interpretation of the results.
Weak acting opioids and opioid agonist / antagonists (step 2 WHO)
Back upstairs
Step 2 of the WHO pain ladder in chronic malignant pain involves the addition of weak opioids and opioid agonist / antagonists in step 1. There is only limited research showing the effectiveness of these resources, both malignant and benign chronic pain. The weak opioids produce similar side effects as morphine, such as nausea and vomiting.
Codeine
The dose equivalent of 15 mg of morphine codeine is 100 mg orally. Such a high dose of codeine is associated with opioid-like side effects, such as nausea, vomiting, respiratory depression, urinary retention, and constipation. Codeine is partly converted in the body into morphine. This conversion is incomplete in patients with a deficiency of the liver enzyme CYP2D6, or concomitant use of drugs that inhibit this enzyme (eg. Cimetidine and fluoxetine). The analgesic effect will diminish in theory. 29 In practice, this is difficult to ascertain, because to another metabolite of codeine, codeine, also an analgesic effect is ascribed. 30 This makes the analgesic effect of codeine variable and unpredictable.
A meta-analysis of studies with several NSAIDs and weak opioids in patients with chronic malignant pain, showed no significant differences in analgesic effect between two groups of resources were at a single administration. 21, significant differences were not found in an observation period of 10 to 14 days. However, the number of patients in the latter assay was minor. Moreover, it was not available in the Netherlands NSAID ketorolac in oral form the means by which was compared. 21
The conclusion is that combinations of paracetamol and codeine for the treatment of chronic malignant and benign pain have a limited place. 1
Dextropropoxyphene is a weakly-active opioid agonist / antagonist. Its application is not recommended, because of the long half-life and the risk of accumulation of a toxic metabolite (nordextropropoxyfeen). 31 There have been many cases of conscious or unconscious overdose of dextropropoxyphene with fatal consequences. It is remarkable how quickly cause death, usually within the hour. 7 A possible respiratory depression may, although difficult (due to the strong receptor binding) are treated with naloxone. There are no randomized controlled trials on the effects of dextropropoxyphene in chronic benign pain. The plea has no place.
Pentazocine is an opioid agonist / antagonist. The agent has no place in the WHO pain ladder: after prior use of pentazocine have other opioid agonists no analgesic effect for hours. Furthermore, there are no randomized controlled studies on the effect of pentazocine in chronic benign pain or chronic malignant pain.
Buprenorphine (sublingual) is a partial agonist of the m-receptor. The agent has a ceiling effect, making dosing higher than the standard dose of 0.4 mg (sublingual) every 6 hours is not useful. Nausea and vomiting occur frequently. An advantage is the possibility of sublingual administration. If a respiratory depression occurs this can only be partly removed by high doses of naloxone. 7 In the transition from buprenorphine to an agent from step 3 are sometimes high doses of the agent needed, probably due to the strong receptor binding of buprenorphine. There is no randomized and controlled trial available in which the effect of buprenorphine was determined in chronic benign pain, nor in chronic malignant pain.
Tramadol has a weak agonist effect on most opioid receptors. Further, it inhibits the reuptake of norepinephrine, and enhances the release of serotonin. It is for that reason be promoted for neurogenic pain, but studies are lacking in this indication. The agent has not been studied in chronic malignant pain. Tramadol is in chronic benign pain not proved better than acetaminophen / codeine. In a study of tramadol was compared with dextropropoxyphene in patients with osteoarthritis of the hip and / or knee tramadol proved no more effective than dextropropoxyphene. 32 In addition, patients who reported tramadol used significantly more side effects. The value of this study is questionable, given the limited duration of two weeks for a chronic condition such as osteoarthritis and compared with dextropropoxyphene. 32
Tramadol is less potent than morphine, while the adverse event profile was similar. A quarter of the patients experienced nausea and constipation. One in five patients reported headache and other central side effects. Confusion and hallucinations were observed in 10% of the patients. 33 In patients with epilepsy caution since been reported after taking tramadol seizures. 33
Strong-acting opioids (step 3 WHO)
Back upstairs
Morphine derivatives and
oral
The introduction of oral morphine sustained-release preparations have significantly facilitated the use of morphine.
Chronic malignant pain
It is common to in patients in whom morphine is indicated to start with a low dose of long-acting morphine, whether or not combined with ordinary morphine tablets. The dosage is dependent on, among other opioid and earlier age.
Another, much used in the Netherlands, method, in order to establish in patients on morphine, is a titration of the dose required with a short-acting morphine preparation. With morphine tablets or ® Juice in dosage units of from 5 to 10 mg every 4 to 6 hours, one can measure the need for morphine. After 48 hours, can then be passed to the equivalent dose of a preparation having delayed release. In order to prevent nausea when setting of the therapy, at the same time can metoclopramide, domperidone or haloperidol are administered. 34 It is necessary to give all patients using opioids prophylactic laxative ( EB 1992: 26: 35-36 ). One starts with an osmotic laxative such as lactulose. In case of insufficient results one gives a contactlaxans, such as bisacodyl or sennoside, there. The "as needed" administration of plain morphine tablets (duration about 4 hours) in addition to those with sustained release, such as when breakthrough pain in cancer patients, it could be considered more often. When this is required more frequently in a day, it is necessary to increase the daily dose of the sustained release excipient. When gradually, in principle, increasing the dose of delayed release means, there is no maximum to the dosage of morphine, because of the tolerance development in respect of a part of the side effects.
Chronic benign pain
There is only one randomized study published on the treatment of chronic benign pain with morphine. It compared the effects of morphine with atropine Benz (placebo) to 61 "end-stage" patients with regional pain from soft tissue or skeletal muscle or rheumatic pain of at least six months. The results, however limited, according to the intention-to-treat principle were analyzed, showed that patients may benefit from the analgesic effect of morphine treatment for nine weeks at doses up to 120 mg / day. This therapy, however, was associated with many side effects and patients did not psychological or functional improvements. 35
In patients with chronic benign pain with a pathologic-anatomical substrate, which do not respond to other analgesics, sometimes remains as a single solution over the use of opioid analgesics. 36 37 As an indication, it applies that 'guidelines for the responsible use of morphine' are respected. An example of such guidelines is listed in Table 2. 35 38 39
Tab. 2 Guidelines prescribe opioids in chronic benign pain
Opioids for writing only if other analgesics (non-opioids) with or without co-analgesics, or adjuvants fail or are contraindicated.
A doctor with special expertise in the treatment of pain in consultation questions to test a responsible use of opioids in benign pain.
Coy with opioids for pain with psychological factors play an important role.
No prescription opioids in patients with addiction pattern for 'resources' for personality disorders and uncontrolled environmental factors.
One doctor (end) responsible for opioid prescription.
The patient is well informed about the risks and benefits of the therapy.
Starting with a trial for some time (eg. One month). During this test, see the patient weekly. The treatment may be prosecuted with adequate analgesia and well-being of the patient.
After the test treatment, the patient see quarterly.
If the desired result is not achieved, patients refer to pain specialist.
Oral therapy is the cornerstone of opioid treatment. By uncontrollable nausea or vomiting consider transdermal therapy. Parenteral therapy is not recommended strongly in general.
Unsanctioned dose escalation with suspected abuse or resale should lead to discontinuation of treatment.
Cooperation by means of reporting back to the pharmacist is urgently needed.
Letting Keeping a pain score (in the pilot phase) is recommended.
The effectiveness of opioids in patients with chronic benign pain without pathological-anatomical substrate has not been studied in randomized controlled trials. Some believe that for patients with intractable chronic benign pain without pathological-anatomical substrate is never an indication for the use of opioid analgesics. 36 40 They consider the prescription of opioid analgesics to these patients as unethical. Such difficult to treat pain is desired, consultation with doctors who specialize in treating patients with chronic pain.
Choice between oral agents
The relationship between the serum concentration of morphine, and the analgesic effect is not be determined unambiguously in patients with chronic pain. The major metabolites of morphine are the glucuronides. The morphine-6-glucuronide has its own analgesic effect that is greater than that of morphine. The morphine-3-glucuronide does not relieve pain, but it is partly responsible for the side effects of morphine. In a double-blind study of 152 patients with chronic malignant pain, the effect of some morphine formulations was compared with sustained release. 41 After one week of treatment, there was no difference in effectiveness and side effects between the compositions. The examination period of one week, however, makes it impossible to make informed judgments about the advantages and disadvantages of the different forms of administration of the sustained-release preparations. 41
Rectal
There is only a limited choice in rectal dosage forms of the opioid. Commercial is a suppository containing 10 mg nicomorphine available and the FNA gives a prescription for morphine suppositories in different strengths. As a result of this limited choice is recommended, the rectal administration of an oral composition with delayed release. In spite of a variable bioavailability this route of administration is sometimes an outcome in patients with chronic malignant pain. 42 43
parenterally
The administration of intravenous, intramuscular or subcutaneous opioids in chronic benign pain is seriously discouraged. A continuous administration of subcutaneous infusion of morphine or hydromorphone (= hydromorphone) is only used in terminal patients with chronic malignant pain in home care programs. Because of its simplicity, this technique is easily applicable for the GP or nursing. 44 If parenteral therapy is contemplated is the administration via a pump system with PCA (patient controlled analgesia) an option. 45 46 The more invasive pain treatment with epidural or intrathecal opioids are reserved to the anesthesiologist. Home care programs with epidural or intrathecal opioids are successfully used for 15 years in our country in oncology. 47-50
Agents which are commonly used epidurally, are morphine, nicomorphine, fentanyl or sufentanil, whether or not in combination with bupivacaine. For the intrathecal administration appears morphine (with or without bupivacaine) are most suitable. 50 The spinal use of opioids is limited to patients with chronic malignant pain orally, intravenously or subcutaneously very high doses need opioids, or situations where the side effects of this administration so require. The availability of oral morphine sustained-release preparations and of the transdermal form of fentanyl, the necessity of the spinal route of administration is decreased over the last few years.
fentanyl
transdermal
The introduction of a transdermal dosage form of fentanyl has shifted the need for rectal and subcutaneous administration of opioids to the background. After an initial fentanyl patch is stuck on or after their dosage is increased, it will take 12 to 24 hours before a constant fentanyl concentrations are reached. Therefore, the initial dose of morphine, yet one has to continue for at least 12 hours. The patient may then proceed with additional morphine orally or rectally if analgesia by the patch is insufficient. This additional medication passes, one in general in a dosage which amounts to one third to one half of the amount of opioid. 46 The patch of the duration of action is 72 hours. For the analgesic effect may occur tolerance. The analgesic effect of the patch is sometimes reduced already after 48 hours, and then it is necessary to change the patch earlier. Due to the formation of fentanyl depot in the subcutaneous fat will, after removal of the patch, the effect for at least 20 hours to be able to keep. 46 In overdose, this is a serious drawback. There is insufficient evidence from double-blind studies that the risk of nausea, vomiting and constipation with this dosage form is less than with others.
However, a major drawback is the controllability of the therapy and the lack of clarity about the conversion factor for equipotent doses of morphine. Initially, between morphine and fentanyl a conversion factor of 150: 1 applied, but now it is clear that a ratio of 70: 1 to 100: 1 is desirable. 46 One of the variables that change, moreover, the effect of the patch, is the ambient temperature. After a hot shower absorption can increase by approximately 35%. In the setup phase, it is in addition to use of an ordinary oral or rectal opioids, therefore, to consider.
The application of fentanyl patch is only recommended in patients with swallowing disorders or severe gastrointestinal intolerance to oral opioids.
methadone
For methadone in pain management little place anymore. The workability of the product is limited by, inter individually highly variable, long-lived. In cancer patients with neurogenic pain which are not adequately respond to (high) doses of morphine has been shown that the transition can have on methadone success. 51 One must do it carefully by slowly tapering the dose of morphine and slowly increase the dose of methadone. The analgesic effect of methadone in neurogenic pain is sometimes attributed to its role as the N-methyl-d-aspartate (NMDA) receptor antagonist. In the treatment of chronic benign pain are no studies with methadone.
Adjuvant drugs in neurogenic pain
Back upstairs
Neurogenic pain is difficult to treat with analgesics, because the classical analgesics, such as NSAIDs or opioids, often do not have the desired effect. Experience has shown that relatively high doses of opioids required for neurogenic pain. As primary or complementary therapy or antidepressants ( EB 1992; 26: 6 ), anticonvulsants, local anesthetics, anti-arrhythmic with a local anesthetic effect (mexiletine) and capsaicin cream applied.
In diabetic neuropathy and post-herpetic neuralgia include tricyclic antidepressants, amitriptyline, and in particular, proved to be effective. 52 is as yet not been established as the selective serotonin re-uptake inhibitors (SSRIs), that these are equivalent to the tricyclic antidepressants. 53 Neurogenic pain usually has a continuous character. In neurogenic pain that occurs paroxysmal, such as trigeminal neuralgia is carbamazepine first choice. 54
In cancer patients with a nerve injury (nerve pain), the cause of this must be taken into account. When nerve pain from a tumor process, as radiculomyelopathie by a spinal or plexopathy by a lymph node metastasis, pain medication indicated by the WHO ladder. 55 It starts given paracetamol or an NSAID and morphine is insufficient effect. When nerve pain as a result of surgical intervention previously, or some other non tumor related to a cause, such as phantom limb pain, postdissectie-pain or post-herpetic neuralgia, amitriptyline is the first choice. If this latter pain respond inadequately to amitriptyline, nortriptyline or desipramine should be considered. When, in particular, lancinerende neurogenic pain, one can write for anticonvulsants, whether or not in combination with tricyclic antidepressants. Carbamazepine and clonazepam are eligible. It is to gradually increase the dosage with regard to the side effects that can occur. By some is also known the use of mexiletine or baclofen recommended as adjunctive agents in the treatment of neuropathic pain in patients with cancer. 31 Mexiletine is registered for the treatment and prevention of ventricular arrhythmias. It has a narrow therapeutic index. The mechanism of action in the treatment of neuropathic pain is unknown and there are insufficient double-blind and randomized studies that justify the use of this agent. The value of the addition of clonidine to epidural bupivacaine or morphine infusions in patients with neuropathic pain has been insufficiently investigated. 31
At SCC caused by epidural metastasis and nerve compression by tumors or metastases corticosteroids may be required ( EB 1992; 26: 21-22 ). In two randomized trials, the efficacy of dexamethasone demonstrated this. 56 57
Local application of capsaicin cream (0.050 to 0.075%) is applicable to post-herpetic neuralgia, diabetic neuropathy and other forms of neuropathic pain. 58 onerous of these are the local irritation and the long time, at least 2 to 4 weeks, before the effect occurs.
Drugs for other types of pain
Back upstairs
Bone pain from metastases
In the treatment of pain due to bone metastases, the most common in patients with cancer pain, radiation therapy should be considered. If it is decided to pharmacotherapy is advised to adhere to the WHO ladder. The efficacy of NSAIDs on bone metastases has not been established in controlled studies. 21 In addition there are several drug options, whose value has been fixed sufficiently in controlled clinical trials. Bisphosphonates are increasingly used in pain caused by bone metastases. In addition to analgesics bisphosphonates are used intravenously or orally. 59 However, this has no direct analgesic effect. Clodronate, pamidronate and alendronate showed a reduction in bone metastases. For etidronate, this effect could not be established. 60
The application of the radiopharmaceuticals strontium chloride Sr 89 and rhenium 186 Re HEDP is an option in patients with painful bone metastases from prostate or breast cancer, if radiation therapy can not be applied and drug therapy provides no or insufficient results. 61 These (expensive) treatment is rarely used; they can be performed in the nuclear medicine department of a hospital only. The response is approximately 80-90%. The effect occurs after 10 to 20 days, with a maximum at six weeks. The effect can last for several months thereafter. The weekly determination of blood counts is necessary because the risk of bone marrow depression is present.
Hurt by severe intestinal spasms
In severe intestinal cramps caused by intestinal obstruction is recommended by some, but the use of octreotide. This means 31 is a synthetic analogue of somatostatin and is registered for the treatment of symptoms associated with acromegaly and in endocrine tumors of the gastrointestinal tract and pancreas. There is no randomized clinical trial has demonstrated the efficacy of this agent.
Reflex sympathetic dystrophy
The treatment of this pain syndrome is difficult. There are insufficient data from randomized double-blind study known to rely on a treatment plan. The treatment is left to a doctor who has specific expertise in the treatment of chronic pain. 62
Summary and Conclusion
Back upstairs
Pain can occur in the context of a malignant disease (chronic malignant pain) and in the context of a non-malignant disease (chronic benign pain). The latter is distinguished in a form with and without an anatomical substrate. Furthermore, the distinction between nociceptive pain and neurogenic of importance, as this may determine the success of a treatment. Nociceptive pain generally responds well to traditional analgesics.
The classic WHO ladder that was developed for the treatment of malignant pain, is now being increasingly promoted for the treatment of nociceptive chronic benign pain. Nociceptive chronic benign pain without pathological-anatomical substrate has not been studied in randomized double-blind study.
In Step 1 of the WHO ladder, it is preferred to acetaminophen for up to 6 g per day, for both nociceptive chronic malignant pain as benign. At insufficient results may be prescribed in Step 1 NSAIDs. The new and the conventional means are effective in chronic benign pain caused by rheumatoid arthritis, but in this work no better than paracetamol. There is no effect of these agents in chronic malignant pain. Furthermore, it is of the newer drugs, the COX-2 inhibitors, thereby not sufficiently demonstrated in randomized double-blind study that they have fewer side effects than the traditional means. If NSAIDs are prescribed thereby, preference is given to ibuprofen, diclofenac, or naproxen in the lowest possible effective dose.
Step 2 of the WHO ladder involves adding weak acting opioids or opioid agonist / antagonists at step 1. The combination of acetaminophen with codeine has in the treatment of chronic malignant and benign pain only a limited place. Dextropropoxyphene and pentazocine have no place in step 2 because of serious side effects. Buprenorphine has been sufficiently studied in chronic malignant and benign pain, in order to be able to give it a place. Tramadol is in chronic benign pain not proved better than acetaminophen / codeine.
Step 3 of the WHO ladder concerns prescribing opioids. These agents are widely used in chronic malignant pain. On the use of opioids in chronic benign pain is to give a ruling, since only one randomized trial was carried out. In patients with chronic malignant pain and difficulty swallowing or severe gastrointestinal intolerance to oral agents the use of transdermal fentanyl can be considered in principle. In chronic malignant pain, there is only limited room for methadone.
When nerve pain from a tumor process is pain medication indicated by the WHO ladder. When nerve pain from another cause is amitriptyline preferred. At lancinerende neurogenic pain anticonvulsants are eligible. The use of mexiletine is not recommended.
For drug treatment of bone pain from metastases are eligible opioids, and bisphosphonates radiopharmaceuticals. The efficacy of NSAIDs is hereby not been demonstrated.
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localized and has a sharp, dull, stabbing or throbbing character. Visceral pain is less localized and has a cramping or oppressive character. Usually responds nociceptive pain conventional analgesics. 6 7
Neurogenic pain, also known as neuropathic pain, arises in case of damage or dysfunction of the nervous system, both peripherally and centrally. 8 It arises after a latency period of days to months, persistent pain with extremely sensitive nociceptors. This usually has a burning, shooting or irritating character. Neurogenic pain is distinguished from nociceptive pain especially by abnormal pain sensations, such as excessive pain in response to a painful stimulus (hyperalgesia), or pain due to a stimulus that normally does not lead to pain (allodynia). This can occur even in a hypervariable region or anesthetic: hyperpathia. Neurogenic pain responds generally poorly to conventional analgesics and can be very difficult to treat. 9
Nociceptive chronic pain and pain ladder
Back upstairs
The general principles in the treatment of chronic malignant pain consist of: Preferably, for oral administration, the use of fixed doses in order to obtain continuous analgesia and the bijtitreren acts as breakthrough pain. The side effects should be discussed with the patient sedation, constipation and nausea / vomiting at the start of treatment. The therapy should be focused on the prevention of and not every time the treating pain.
Step 1: Non-opioids with or without adjuvant therapy
Step 2: opioids for moderate pain with funds from step 1
Step 3: opioids for moderate to severe pain with funds from step 1
Some experts recommend that in the treatment of pain or to skip step 2 of the ladder pain in the treatment of chronic malignant pain. One reason for not doing this is that it would have an emotional significance for many patients when they fairly quickly after step 1 'need to morphine. A recently published survey shows that Dutch doctors are relatively reluctant to prescribe morphine for pain. Doctors in Britain and the Scandinavian countries write three to eight times more morphine than their Dutch counterparts. 10 Opioids in patients with chronic malignant pain rarely addictive and 'opiofobie' is therefore no place. This 'opiofobie' may namely lead to undertreatment or setting too late to opioid therapy in patients with chronic malignant pain. 11-13 It is not known whether the same is also true for chronic benign pain.
The classic WHO ladder is increasingly also advocated for nociceptive chronic benign pain. In the remainder of this article will particularly examine the results of the clinical study with analgesics in this indication.
Paracetamol and NSAIDs (step 1 WHO)
Back upstairs
Paracetamol and NSAIDs have an analgesic and antipyretic effects. The NSAIDs, including acetylsalicylic acid, in addition, have an antiphlogistic effect. The term peripheral analgesics for this group of drugs is no longer used. One begins preferably with paracetamol and insufficient effect may be considered an NSAID.
Paracetamol
For patients with chronic malignant pain there is a maximum dose of 1g every 4 hours, 14 is usually a daily dose of from 3 to 4 g adequate. In practice, often paracetamol dose too low for fear of possible liver damage. In chronic pain can be applied doses to 6 g per day. With excessive alcohol consumption and intake of more than 6 g acetaminophen suddenly there is an absolute risk of liver damage. The bioavailability of rectally administered paracetamol is equal to that of the oral administration. However, the rate of absorption upon rectal administration, is less than for oral administration. This means that in case of chronic administration, similar doses of paracetamol given orally and rectally, are equally effective. In chronic benign pain is paracetamol first choice.
NSAIDs
There have been generating strong evidence that NSAIDs their peripheral analgesic effects partly via the central nervous system. That, NSAIDs central effects, was already known because of the central side effects, including headache (so-called. Analgesic headache), dizziness and tinnitus. 15
According to current views NSAIDs inhibit the enzyme cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The inhibition of COX-1 is potentially relevant to the (adverse) effects on the gastro-intestinal wall, the kidney flow, the vessels (hypertension), and the platelet aggregation. The inhibition of COX-2 is strongly related to the anti-inflammatory effect. This has led to the development of so-called COX-2-selective NSAIDs, which in the Netherlands meloxicam ( EB 1996; 30: 119-120 and 1997; 31: 38 ) and nabumetone Gebu 1994; 28: 48 ) are registered. In randomized controlled trials did not show that the newer NSAIDs have better efficacy than the more traditional means. A review article shows that in some studies but not in other studies not significantly fewer gastrointestinal side effects such as ulcers and erosions, of meloxicam have been demonstrated in patients with rheumatoid arthritis and coxarthrosis. 16 In these studies, however, non-equivalent dosages compared or was compared with agents that have a high risk of gastrointestinal side-effects, such as piroxicam. Meloxicam also can cause serious gastrointestinal events ( EB 1998; 32: 38 ). Of nabumetone has been shown in a few studies that it works just as effectively as ibuprofen, naproxen and diclofenac in the treatment of patients with rheumatoid arthritis or osteoarthritis. 17-19 Nabumetone would in these studies significantly fewer side effects on the gastric mucosa than other means. The structure of two of these studies, 17 18, however, leaves much to be desired, since there was compared with non-equivalent dosages of the conventional means. Meloxicam and nabumetone have fewer side effects, has not been shown in randomized double-blind study. A recent published cohort study ( EB 1998; 32: 63 and 100 ) are indications obtained which nabumetone, like ibuprofen, diclofenac, indomethacin and naproxen has the lowest risk of gastrointestinal side effects. 20 If NSAIDs are prescribed, the preference is for agents with the smallest risk of side effects, such as ibuprofen, diclofenac, or naproxen ( EB 1994; 28: 85-86 ) and possible nabumetone.
The clinical impression of experts in the treatment of pain is that NSAIDs have an added value in bone pain. A meta-analysis of the efficacy and safety However, it appears that an added value of classic NSAIDs has never been convincingly demonstrated by bone metastases. 21 from both the classical and the new resources not show any effect in controlled clinical trials in malignant pain, nor in non-malignant pain other than rheumatoid aandoeningen.2 Therefore, no statement can be made about the use of selective COX-2 inhibitors with pain that is not caused by rheumatoid arthritis. 22
In the treatment of chronic benign pain is the value of NSAIDs over acetaminophen, as regards the reduction of pain, not convincingly demonstrated. In a review of controlled clinical trials in the field of pharmacotherapy in gonarthrosis concluded that both NSAID and paracetamol is more effective than placebo. The effect of paracetamol is comparable to that of ibuprofen or naproxen. 23 Chronic use of NSAIDs should, especially given the risk of renal papillary necrosis and chronic renal failure are not recommended in patients older than 75 years, diuretics, liver cirrhosis or kidney disease. 24 25
NSAIDs in patients at risk
Two studies published in patients with joint disorders (particularly rheumatoid arthritis and osteoarthritis) requiring chronic NSAID and also had stomach ulcers or erosions in the stomach and / or duodenum, where the healing and protective effect of omeprazole compared with ranitidine and misoprostol. 26 27 Omeprazole cured the defects significantly better than ranitidine 26 and as effective as misoprostol. 27 Omeprazole protected significantly better than misoprostol. the authors have failed in both studies mentioned above indicate which type of NSAID used the patients. Furthermore, they have not been investigated or the prognosis, i.e., the side effects and the risk of recurrence, is dependent on the kind of NSAID that the patients used.
Local NSAIDs
In a recent meta-analysis of clinical trials in patients with acute and chronic pain as a result of a mono-arthritis or rheumatoid arthritis, bleaching topically applied NSAID's work to be significantly more effective than placebo. The local and systemic adverse events were similar to placebo. 28 However, the average observation period of the trials was only two weeks. Furthermore, no proper comparison could be made with oral NSAIDs, as the quality of those studies was too small. This complicates the interpretation of the results.
Weak acting opioids and opioid agonist / antagonists (step 2 WHO)
Back upstairs
Step 2 of the WHO pain ladder in chronic malignant pain involves the addition of weak opioids and opioid agonist / antagonists in step 1. There is only limited research showing the effectiveness of these resources, both malignant and benign chronic pain. The weak opioids produce similar side effects as morphine, such as nausea and vomiting.
Codeine
The dose equivalent of 15 mg of morphine codeine is 100 mg orally. Such a high dose of codeine is associated with opioid-like side effects, such as nausea, vomiting, respiratory depression, urinary retention, and constipation. Codeine is partly converted in the body into morphine. This conversion is incomplete in patients with a deficiency of the liver enzyme CYP2D6, or concomitant use of drugs that inhibit this enzyme (eg. Cimetidine and fluoxetine). The analgesic effect will diminish in theory. 29 In practice, this is difficult to ascertain, because to another metabolite of codeine, codeine, also an analgesic effect is ascribed. 30 This makes the analgesic effect of codeine variable and unpredictable.
A meta-analysis of studies with several NSAIDs and weak opioids in patients with chronic malignant pain, showed no significant differences in analgesic effect between two groups of resources were at a single administration. 21, significant differences were not found in an observation period of 10 to 14 days. However, the number of patients in the latter assay was minor. Moreover, it was not available in the Netherlands NSAID ketorolac in oral form the means by which was compared. 21
The conclusion is that combinations of paracetamol and codeine for the treatment of chronic malignant and benign pain have a limited place. 1
Dextropropoxyphene is a weakly-active opioid agonist / antagonist. Its application is not recommended, because of the long half-life and the risk of accumulation of a toxic metabolite (nordextropropoxyfeen). 31 There have been many cases of conscious or unconscious overdose of dextropropoxyphene with fatal consequences. It is remarkable how quickly cause death, usually within the hour. 7 A possible respiratory depression may, although difficult (due to the strong receptor binding) are treated with naloxone. There are no randomized controlled trials on the effects of dextropropoxyphene in chronic benign pain. The plea has no place.
Pentazocine is an opioid agonist / antagonist. The agent has no place in the WHO pain ladder: after prior use of pentazocine have other opioid agonists no analgesic effect for hours. Furthermore, there are no randomized controlled studies on the effect of pentazocine in chronic benign pain or chronic malignant pain.
Buprenorphine (sublingual) is a partial agonist of the m-receptor. The agent has a ceiling effect, making dosing higher than the standard dose of 0.4 mg (sublingual) every 6 hours is not useful. Nausea and vomiting occur frequently. An advantage is the possibility of sublingual administration. If a respiratory depression occurs this can only be partly removed by high doses of naloxone. 7 In the transition from buprenorphine to an agent from step 3 are sometimes high doses of the agent needed, probably due to the strong receptor binding of buprenorphine. There is no randomized and controlled trial available in which the effect of buprenorphine was determined in chronic benign pain, nor in chronic malignant pain.
Tramadol has a weak agonist effect on most opioid receptors. Further, it inhibits the reuptake of norepinephrine, and enhances the release of serotonin. It is for that reason be promoted for neurogenic pain, but studies are lacking in this indication. The agent has not been studied in chronic malignant pain. Tramadol is in chronic benign pain not proved better than acetaminophen / codeine. In a study of tramadol was compared with dextropropoxyphene in patients with osteoarthritis of the hip and / or knee tramadol proved no more effective than dextropropoxyphene. 32 In addition, patients who reported tramadol used significantly more side effects. The value of this study is questionable, given the limited duration of two weeks for a chronic condition such as osteoarthritis and compared with dextropropoxyphene. 32
Tramadol is less potent than morphine, while the adverse event profile was similar. A quarter of the patients experienced nausea and constipation. One in five patients reported headache and other central side effects. Confusion and hallucinations were observed in 10% of the patients. 33 In patients with epilepsy caution since been reported after taking tramadol seizures. 33
Strong-acting opioids (step 3 WHO)
Back upstairs
Morphine derivatives and
oral
The introduction of oral morphine sustained-release preparations have significantly facilitated the use of morphine.
Chronic malignant pain
It is common to in patients in whom morphine is indicated to start with a low dose of long-acting morphine, whether or not combined with ordinary morphine tablets. The dosage is dependent on, among other opioid and earlier age.
Another, much used in the Netherlands, method, in order to establish in patients on morphine, is a titration of the dose required with a short-acting morphine preparation. With morphine tablets or ® Juice in dosage units of from 5 to 10 mg every 4 to 6 hours, one can measure the need for morphine. After 48 hours, can then be passed to the equivalent dose of a preparation having delayed release. In order to prevent nausea when setting of the therapy, at the same time can metoclopramide, domperidone or haloperidol are administered. 34 It is necessary to give all patients using opioids prophylactic laxative ( EB 1992: 26: 35-36 ). One starts with an osmotic laxative such as lactulose. In case of insufficient results one gives a contactlaxans, such as bisacodyl or sennoside, there. The "as needed" administration of plain morphine tablets (duration about 4 hours) in addition to those with sustained release, such as when breakthrough pain in cancer patients, it could be considered more often. When this is required more frequently in a day, it is necessary to increase the daily dose of the sustained release excipient. When gradually, in principle, increasing the dose of delayed release means, there is no maximum to the dosage of morphine, because of the tolerance development in respect of a part of the side effects.
Chronic benign pain
There is only one randomized study published on the treatment of chronic benign pain with morphine. It compared the effects of morphine with atropine Benz (placebo) to 61 "end-stage" patients with regional pain from soft tissue or skeletal muscle or rheumatic pain of at least six months. The results, however limited, according to the intention-to-treat principle were analyzed, showed that patients may benefit from the analgesic effect of morphine treatment for nine weeks at doses up to 120 mg / day. This therapy, however, was associated with many side effects and patients did not psychological or functional improvements. 35
In patients with chronic benign pain with a pathologic-anatomical substrate, which do not respond to other analgesics, sometimes remains as a single solution over the use of opioid analgesics. 36 37 As an indication, it applies that 'guidelines for the responsible use of morphine' are respected. An example of such guidelines is listed in Table 2. 35 38 39
Tab. 2 Guidelines prescribe opioids in chronic benign pain
Opioids for writing only if other analgesics (non-opioids) with or without co-analgesics, or adjuvants fail or are contraindicated.
A doctor with special expertise in the treatment of pain in consultation questions to test a responsible use of opioids in benign pain.
Coy with opioids for pain with psychological factors play an important role.
No prescription opioids in patients with addiction pattern for 'resources' for personality disorders and uncontrolled environmental factors.
One doctor (end) responsible for opioid prescription.
The patient is well informed about the risks and benefits of the therapy.
Starting with a trial for some time (eg. One month). During this test, see the patient weekly. The treatment may be prosecuted with adequate analgesia and well-being of the patient.
After the test treatment, the patient see quarterly.
If the desired result is not achieved, patients refer to pain specialist.
Oral therapy is the cornerstone of opioid treatment. By uncontrollable nausea or vomiting consider transdermal therapy. Parenteral therapy is not recommended strongly in general.
Unsanctioned dose escalation with suspected abuse or resale should lead to discontinuation of treatment.
Cooperation by means of reporting back to the pharmacist is urgently needed.
Letting Keeping a pain score (in the pilot phase) is recommended.
The effectiveness of opioids in patients with chronic benign pain without pathological-anatomical substrate has not been studied in randomized controlled trials. Some believe that for patients with intractable chronic benign pain without pathological-anatomical substrate is never an indication for the use of opioid analgesics. 36 40 They consider the prescription of opioid analgesics to these patients as unethical. Such difficult to treat pain is desired, consultation with doctors who specialize in treating patients with chronic pain.
Choice between oral agents
The relationship between the serum concentration of morphine, and the analgesic effect is not be determined unambiguously in patients with chronic pain. The major metabolites of morphine are the glucuronides. The morphine-6-glucuronide has its own analgesic effect that is greater than that of morphine. The morphine-3-glucuronide does not relieve pain, but it is partly responsible for the side effects of morphine. In a double-blind study of 152 patients with chronic malignant pain, the effect of some morphine formulations was compared with sustained release. 41 After one week of treatment, there was no difference in effectiveness and side effects between the compositions. The examination period of one week, however, makes it impossible to make informed judgments about the advantages and disadvantages of the different forms of administration of the sustained-release preparations. 41
Rectal
There is only a limited choice in rectal dosage forms of the opioid. Commercial is a suppository containing 10 mg nicomorphine available and the FNA gives a prescription for morphine suppositories in different strengths. As a result of this limited choice is recommended, the rectal administration of an oral composition with delayed release. In spite of a variable bioavailability this route of administration is sometimes an outcome in patients with chronic malignant pain. 42 43
parenterally
The administration of intravenous, intramuscular or subcutaneous opioids in chronic benign pain is seriously discouraged. A continuous administration of subcutaneous infusion of morphine or hydromorphone (= hydromorphone) is only used in terminal patients with chronic malignant pain in home care programs. Because of its simplicity, this technique is easily applicable for the GP or nursing. 44 If parenteral therapy is contemplated is the administration via a pump system with PCA (patient controlled analgesia) an option. 45 46 The more invasive pain treatment with epidural or intrathecal opioids are reserved to the anesthesiologist. Home care programs with epidural or intrathecal opioids are successfully used for 15 years in our country in oncology. 47-50
Agents which are commonly used epidurally, are morphine, nicomorphine, fentanyl or sufentanil, whether or not in combination with bupivacaine. For the intrathecal administration appears morphine (with or without bupivacaine) are most suitable. 50 The spinal use of opioids is limited to patients with chronic malignant pain orally, intravenously or subcutaneously very high doses need opioids, or situations where the side effects of this administration so require. The availability of oral morphine sustained-release preparations and of the transdermal form of fentanyl, the necessity of the spinal route of administration is decreased over the last few years.
fentanyl
transdermal
The introduction of a transdermal dosage form of fentanyl has shifted the need for rectal and subcutaneous administration of opioids to the background. After an initial fentanyl patch is stuck on or after their dosage is increased, it will take 12 to 24 hours before a constant fentanyl concentrations are reached. Therefore, the initial dose of morphine, yet one has to continue for at least 12 hours. The patient may then proceed with additional morphine orally or rectally if analgesia by the patch is insufficient. This additional medication passes, one in general in a dosage which amounts to one third to one half of the amount of opioid. 46 The patch of the duration of action is 72 hours. For the analgesic effect may occur tolerance. The analgesic effect of the patch is sometimes reduced already after 48 hours, and then it is necessary to change the patch earlier. Due to the formation of fentanyl depot in the subcutaneous fat will, after removal of the patch, the effect for at least 20 hours to be able to keep. 46 In overdose, this is a serious drawback. There is insufficient evidence from double-blind studies that the risk of nausea, vomiting and constipation with this dosage form is less than with others.
However, a major drawback is the controllability of the therapy and the lack of clarity about the conversion factor for equipotent doses of morphine. Initially, between morphine and fentanyl a conversion factor of 150: 1 applied, but now it is clear that a ratio of 70: 1 to 100: 1 is desirable. 46 One of the variables that change, moreover, the effect of the patch, is the ambient temperature. After a hot shower absorption can increase by approximately 35%. In the setup phase, it is in addition to use of an ordinary oral or rectal opioids, therefore, to consider.
The application of fentanyl patch is only recommended in patients with swallowing disorders or severe gastrointestinal intolerance to oral opioids.
methadone
For methadone in pain management little place anymore. The workability of the product is limited by, inter individually highly variable, long-lived. In cancer patients with neurogenic pain which are not adequately respond to (high) doses of morphine has been shown that the transition can have on methadone success. 51 One must do it carefully by slowly tapering the dose of morphine and slowly increase the dose of methadone. The analgesic effect of methadone in neurogenic pain is sometimes attributed to its role as the N-methyl-d-aspartate (NMDA) receptor antagonist. In the treatment of chronic benign pain are no studies with methadone.
Adjuvant drugs in neurogenic pain
Back upstairs
Neurogenic pain is difficult to treat with analgesics, because the classical analgesics, such as NSAIDs or opioids, often do not have the desired effect. Experience has shown that relatively high doses of opioids required for neurogenic pain. As primary or complementary therapy or antidepressants ( EB 1992; 26: 6 ), anticonvulsants, local anesthetics, anti-arrhythmic with a local anesthetic effect (mexiletine) and capsaicin cream applied.
In diabetic neuropathy and post-herpetic neuralgia include tricyclic antidepressants, amitriptyline, and in particular, proved to be effective. 52 is as yet not been established as the selective serotonin re-uptake inhibitors (SSRIs), that these are equivalent to the tricyclic antidepressants. 53 Neurogenic pain usually has a continuous character. In neurogenic pain that occurs paroxysmal, such as trigeminal neuralgia is carbamazepine first choice. 54
In cancer patients with a nerve injury (nerve pain), the cause of this must be taken into account. When nerve pain from a tumor process, as radiculomyelopathie by a spinal or plexopathy by a lymph node metastasis, pain medication indicated by the WHO ladder. 55 It starts given paracetamol or an NSAID and morphine is insufficient effect. When nerve pain as a result of surgical intervention previously, or some other non tumor related to a cause, such as phantom limb pain, postdissectie-pain or post-herpetic neuralgia, amitriptyline is the first choice. If this latter pain respond inadequately to amitriptyline, nortriptyline or desipramine should be considered. When, in particular, lancinerende neurogenic pain, one can write for anticonvulsants, whether or not in combination with tricyclic antidepressants. Carbamazepine and clonazepam are eligible. It is to gradually increase the dosage with regard to the side effects that can occur. By some is also known the use of mexiletine or baclofen recommended as adjunctive agents in the treatment of neuropathic pain in patients with cancer. 31 Mexiletine is registered for the treatment and prevention of ventricular arrhythmias. It has a narrow therapeutic index. The mechanism of action in the treatment of neuropathic pain is unknown and there are insufficient double-blind and randomized studies that justify the use of this agent. The value of the addition of clonidine to epidural bupivacaine or morphine infusions in patients with neuropathic pain has been insufficiently investigated. 31
At SCC caused by epidural metastasis and nerve compression by tumors or metastases corticosteroids may be required ( EB 1992; 26: 21-22 ). In two randomized trials, the efficacy of dexamethasone demonstrated this. 56 57
Local application of capsaicin cream (0.050 to 0.075%) is applicable to post-herpetic neuralgia, diabetic neuropathy and other forms of neuropathic pain. 58 onerous of these are the local irritation and the long time, at least 2 to 4 weeks, before the effect occurs.
Drugs for other types of pain
Back upstairs
Bone pain from metastases
In the treatment of pain due to bone metastases, the most common in patients with cancer pain, radiation therapy should be considered. If it is decided to pharmacotherapy is advised to adhere to the WHO ladder. The efficacy of NSAIDs on bone metastases has not been established in controlled studies. 21 In addition there are several drug options, whose value has been fixed sufficiently in controlled clinical trials. Bisphosphonates are increasingly used in pain caused by bone metastases. In addition to analgesics bisphosphonates are used intravenously or orally. 59 However, this has no direct analgesic effect. Clodronate, pamidronate and alendronate showed a reduction in bone metastases. For etidronate, this effect could not be established. 60
The application of the radiopharmaceuticals strontium chloride Sr 89 and rhenium 186 Re HEDP is an option in patients with painful bone metastases from prostate or breast cancer, if radiation therapy can not be applied and drug therapy provides no or insufficient results. 61 These (expensive) treatment is rarely used; they can be performed in the nuclear medicine department of a hospital only. The response is approximately 80-90%. The effect occurs after 10 to 20 days, with a maximum at six weeks. The effect can last for several months thereafter. The weekly determination of blood counts is necessary because the risk of bone marrow depression is present.
Hurt by severe intestinal spasms
In severe intestinal cramps caused by intestinal obstruction is recommended by some, but the use of octreotide. This means 31 is a synthetic analogue of somatostatin and is registered for the treatment of symptoms associated with acromegaly and in endocrine tumors of the gastrointestinal tract and pancreas. There is no randomized clinical trial has demonstrated the efficacy of this agent.
Reflex sympathetic dystrophy
The treatment of this pain syndrome is difficult. There are insufficient data from randomized double-blind study known to rely on a treatment plan. The treatment is left to a doctor who has specific expertise in the treatment of chronic pain. 62
Summary and Conclusion
Back upstairs
Pain can occur in the context of a malignant disease (chronic malignant pain) and in the context of a non-malignant disease (chronic benign pain). The latter is distinguished in a form with and without an anatomical substrate. Furthermore, the distinction between nociceptive pain and neurogenic of importance, as this may determine the success of a treatment. Nociceptive pain generally responds well to traditional analgesics.
The classic WHO ladder that was developed for the treatment of malignant pain, is now being increasingly promoted for the treatment of nociceptive chronic benign pain. Nociceptive chronic benign pain without pathological-anatomical substrate has not been studied in randomized double-blind study.
In Step 1 of the WHO ladder, it is preferred to acetaminophen for up to 6 g per day, for both nociceptive chronic malignant pain as benign. At insufficient results may be prescribed in Step 1 NSAIDs. The new and the conventional means are effective in chronic benign pain caused by rheumatoid arthritis, but in this work no better than paracetamol. There is no effect of these agents in chronic malignant pain. Furthermore, it is of the newer drugs, the COX-2 inhibitors, thereby not sufficiently demonstrated in randomized double-blind study that they have fewer side effects than the traditional means. If NSAIDs are prescribed thereby, preference is given to ibuprofen, diclofenac, or naproxen in the lowest possible effective dose.
Step 2 of the WHO ladder involves adding weak acting opioids or opioid agonist / antagonists at step 1. The combination of acetaminophen with codeine has in the treatment of chronic malignant and benign pain only a limited place. Dextropropoxyphene and pentazocine have no place in step 2 because of serious side effects. Buprenorphine has been sufficiently studied in chronic malignant and benign pain, in order to be able to give it a place. Tramadol is in chronic benign pain not proved better than acetaminophen / codeine.
Step 3 of the WHO ladder concerns prescribing opioids. These agents are widely used in chronic malignant pain. On the use of opioids in chronic benign pain is to give a ruling, since only one randomized trial was carried out. In patients with chronic malignant pain and difficulty swallowing or severe gastrointestinal intolerance to oral agents the use of transdermal fentanyl can be considered in principle. In chronic malignant pain, there is only limited room for methadone.
When nerve pain from a tumor process is pain medication indicated by the WHO ladder. When nerve pain from another cause is amitriptyline preferred. At lancinerende neurogenic pain anticonvulsants are eligible. The use of mexiletine is not recommended.
For drug treatment of bone pain from metastases are eligible opioids, and bisphosphonates radiopharmaceuticals. The efficacy of NSAIDs is hereby not been demonstrated.
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