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Tramadol for acute Pain

February 10th, 2009

Although tramadol has been used in myocardial emergencies, in trauma and obstetric pain, or to supplement balanced anaesthesia, most studies have investigated postoperative patients.

The focus of this article is to review clinical experience with tramadol in the treatment of acute postoperative pain.

 Tramadol, a synthetic opioid of the aminocyclohexanol group, is a centrally acting analgesic with weak opioid agonist properties, and effects on noradrenergic and serotonergic neurotransmission. In addition, these opioid and nonopioid modes of action appear to act synergistically.

Tramadol has been shown to provide effective analgesia after both intramuscular and intravenous administration for the treatment of postoperative pain. The drug is available in formulations suitable for oral, rectal and parenteral administration. Clinically effective analgesic doses of tramadol were comparable to those of pethidine (meperidine) and about 10 times higher than those of morphine. While it is not recommended as a supplement to general anaesthesia because of its insufficient sedative activity, tramadol has been successful in the treatment of postoperative pain. A randomised double-blind study reported acceptable analgesia with postoperative intravenous tramadol 50mg, repeated once if required after 30 minutes.

It produced an effect similar to that of morphine 5mg or the alpha 2 agonist, clonidine 150 micrograms. In another study, it was shown that the 50mg dose of tramadol fulfilled the requirements of an analgesic for the treatment of moderate postoperative pain, whereas for severe pain a higher dose was recommended. Tramadol is generally well tolerated, the most common adverse events being nausea and vomiting.

In contrast to agents such as morphine and pethidine, clinically relevant respiratory depression is rarely observed during tramadol administration at equipotent doses and consequently it can be recommended for first-line management of postoperative pain instead of morphine. It is also associated with a low incidence of cardiac depression and significantly less dizziness and drowsiness than morphine. Finally, the dependence and abuse potential with tramadol is negligible.

Comparative studies have generally shown that tramadol is more effective than NSAIDs for controlling post operative pain. Use of a combination of tramadol and NSAIDs allows the tramadol dose to be reduced and results in a lower incidence of adverse effects. Patient controlled analgesia (PCA) with tramadol has been frequently used and is well accepted by patients. Wide individual variations exist with regard to analgesic requirements and, nowadays, it is generally accepted that adequate pain management implies systematic individualisation of the therapy, i.e. titration of the analgesic effect to individual needs. Demand and loading doses play a decisive role in the success of PCA.

Analgesic failures requiring rescue medication are rare, but it should be stressed that these can always occur with weak opioids. In conclusion, tramadol can be recommended as a basic analgesic for the treatment of moderate to severe pain. In the event of analgesic failure with tramadol, there is no reason not to switch to more potent opioids. Although no studies are available regarding its use in the management of postoperative pain after day case surgery, tramadol is frequently administered with good results in such patients. The most important side effects of tramadol are nausea and emesis, which can often be prevented by slow injection and administration of a prophylactic antiemetic such as metoclopramide.

Tramadol is a weak opioid analgesic with a potency comparable to that of pethidine. While it is not recommended as a supplement to general anaesthesia because of its insufficient sedative activity, tramadol has been successful in the treatment of postoperative pain. Several studies have demonstrated its analgesic efficacy after intramuscular and intravenous application, both in adults and children. Moreover, negligible respiratory depressant activity and only minor side effects have consistently been shown. Patient-controlled analgesia with tramadol has been frequently employed and was well accepted by the patients. There have been only a few studies of oral or spinal application of tramadol in acute pain states. Tramadol has also been used for the control of pain associated with labour and acute myocardial infarction, as well as for the management of trauma pain. In summary, tramadol can be recommended as a basic analgesic for the treatment of patients with moderate to severe pain.

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Tramadol Efficacy

February 10th, 2009

Tramadol (Tramal™) is a synthetic, centrally-acting analgesic used parenterally and orally for the treatment of moderate to severe pain. 

In 1998, tramadol became the most used centrally-acting analgesic worldwide; outselling morphine in dollars turned over.1 The success of tramadol is mainly a result of its favourable side effect profile, which differs significantly from that of other opioids.

Tramadol efficacy in a broad range of painful conditions

Tramadol has a dose-dependent efficacy that lies between that of codeine and morphine, with a parenteral potency comparable to that of pethidine, i.e. about 10-20% of the gold standard morphine. Oral bioavailability is high (85-100%) and permits easy conversion from the oral to the parenteral route and visa versa.  Surprisingly, the efficacy of tramadol is not associated with the usual serious opioid side effects which can often be dose-limiting.  Furthermore, unlike nonsteroidal anti-inflammatory drugs, tramadol has no serious adverse gastrointestinal effects, such as gastrointestinal bleeding.  Numerous clinical trials have proven its efficacy and safety over a broad range of painful conditions, both acute and chronic; however, in severe pain morphine may be superior to tramadol. It is this combination of safety with good efficacy that has made tramadol a unique addition to the analgesic armamentarium.

Tramadol efficacy in different pain situations

Tramadol is a synthetic analogue of codeine that binds to mu opiate receptors and inhibits norepinephrine and serotonin reuptake. It is rapidly and extensively absorbed after oral doses and is metabolized in the liver. Analgesia begins within one hour and starts to peak in two hours. In patients with moderate postoperative pain, i.v. or i.m. tramadol is roughly equal in efficacy to meperidine or morphine; for severe acute pain, tramadol is less effective than morphine.

Oral tramadol can also be effective after certain types of surgery. Tramadol and meperidine are equally effective in postoperative patient-controlled analgesia. In epidural administration for pain after abdominal surgery, tramadol is more effective than bupivacaine but less effective than morphine. In patients with ureteral calculi, both dipyrone and butylscopolamine are more effective than tramadol. For labor pain, i.m. tramadol works as well as meperidine and is less likely to cause neonatal respiratory depression.

Oral tramadol is as effective as codeine for acute dental pain. In several types of severe or refractory cancer pain, tramadol is effective, but less so than morphine; for other types of chronic pain, such as low-back pain, oral tramadol works as well as acetaminophen-codeine. Common adverse effects of tramadol include dizziness, nausea, dry mouth, and sedation. The abuse potential seems low. The recommended oral dosage is 50-100 mg every four to six hours. Tramadol is an effective, if expensive, alternative to other analgesics in some clinical situations.

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Tramadol pharmacodynamic properties on Pain

February 10th, 2009

Tramadol (CAS 36282-47-0) plays an important role in the management of pain.

With its dual mechanism of action (opioid agonist; weak noradrenaline and serotonin reuptake inhibitor) tramadol provides a kind of combined/adjuvant pain therapy. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids.

Following oral administration the bioavailability of tramadol is high (70-90%) and with new slow release preparations twice daily administration enables effective pain control.

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management. It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in those patients presenting at the onset with moderate-to-severe pain in favor of Step 2 or Step 3. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given “by mouth, by the clock, by the ladder, and for the individual.”  This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for each patient’s individual circumstances and physical condition.

Tramadol is characterised by low plasma protein binding (20%) and quite extensive tissue distribution (apparent volume of distribution about 3 l/kg). Elimination is primarily by the hepatic route (metabolism by CYP2D6 to an active metabolite and by CYP3A4 and CYP2B6) and partly by the renal route (up to 30% of dose). Elimination half-lives of the active agents range between 4.5 and 9.5 h and total plasma clearance of tramadol is moderately high (600 ml/min).

The interaction potential of tramadol is neglectable, as it does not affect the disposition of other drugs. It should be taken into account that inducers (e.g. carbamazepine) or inhibitors (e.g. quinidine for CY2D6) of drug metabolism might modify the elimination of tramadol. Likewise, if kidney (creatinine clearance below 30 ml/min) or hepatic function is severely impaired, some dosage reduction (approximately by 50%) or extension of the dosage interval should be considered.

In conclusion, tramadol is an effective and safe analgesic with a very low interaction potential. Therefore it represents a drug of first choice if moderate to severe pain states have to be treated in pediatric, adult and elderly patients including those with poor cardiopulmonary function.

Opioids

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration-tolerance and physical dependence-are often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain.

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician’s fear of shortening life by increasing opioid doses is usually unfounded.

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