TRAMADOL-GUIDE

The ultram mechanism as described above is very similar to the mechanism employed by narcotics. Acetaminophen of course is the active ingredient in Tylenol. It works by increasing the threshold to pain (i.e. it takes more pain stimulus to cause the sensation of pain). These two drugs work by different mechanisms, and they combine to be more effective than either drug alone.

Pain relief medication can be ordered safely online, but one should exercise appropriate caution before doing so. Specifically, it’s important to determine whether you need to see a physician before ordering pain medication. If you have a sudden onset of pain which is not readily explained, you should consult a physician first. If in doubt, go to the emergency room. If however you are a patient who has been diagnosed, and pain is a recurring problem, you can conveniently order pain medication online- typically at a lower cost than the combined cost of a doctor’s appointment and the medication itself.

Ultram is not considered a controlled substance in the US and is available with a normal prescription. It is considered a controlled substance in Australia. Tramadol is available over the counter without prescription in a few countries. Sweden has, as of May 2008, chosen to classify Tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time. As of December 5th, 2008, Kentucky has classified Tramadol as a C-IV controlled substance. Ultram is sometimes mistakenly classified as an opiate, because of its agonist activity at the µ-opioid receptor; however, chemically it is not related to opiates.

Physical dependence and withdrawal

Ultram is associated with the development of a physical dependence and a withdrawal syndrome. Tramadol causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal effects are probably related to the effect of Ultram on serotonin and norepinephrin reuptake. Symptoms may include anxiety, anguish, pins and needles, sweating, and palpitations. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and when the time comes to discontinue tramadol that they do so gradually over a period of time which will vary according to the individual patient, dose and length of time on the drug.

Psychological dependence and drug misuse

Some controversy exists regarding the dependence/addiction liability of tramadol. Grünenthal has promoted it as an opioid with a lower risk of opioid dependence than that of traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at µ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.

Studies into the dependence liability of Ultram show that patients are no more likely to abuse the drug than normal NSAIDs. Despite these claims, it is apparent in community practice that dependence to this agent may occur, but in higher doses and long-term usage. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like opioids (Rossi, 2004). Similarly, tramadol and Ultram are not currently scheduled by the U.S. Drug Enforcement Agency, unlike opioid analgesics. It is, however, scheduled in certain states. Nevertheless, the prescribing information for Ultram warns that tramadol “may induce psychological and physical dependence of the morphine-type.” A controlled study that compared different medications found “the percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the dependency algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone. This means that the abuse liability of tramadol was almost the same as that of normal NSAIDs, such as ibuprofen.

However, due to the possibility of convulsions at high doses, recreational use is very dangerous. Tramadol can however, via agonism of µ opioid receptors, produce effects similar to those of other opioids (e.g., morphine or hydrocodone), although not nearly as intense due to tramadol’s much lower affinity for the receptor. However, the metabolite M1 is produced after demethylation of the drug in the liver. The M1 metabolite has an estimated 200x greater affinity for the µ1, and µ2 opioid receptors. In addition to acting as an opioid, Ultramis also a very weak but rapidly acting serotonin-norepinephrine reuptake inhibitor. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates which could deter abuse to some extent. Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to lower the quantity of its usage, compared with opiates such as hydrocodone and oxycodone. It may also have large effect on sleeping patterns. High doses may prevent sleeping.

Tramadol has a pregnancy category C, which indicates that animal studies have demonstrated its use to be dangerous during pregnancy and human studies are lacking. Therefore, the drug should not be taken by women who are pregnant unless “the potential benefits outweigh the risks”.

Ultram causes serious or fatal side effects in a newborn, including neonatal withdrawal syndrome, if the mother uses the medication during pregnancy or labor. Use of tramadol by nursing mothers is not recommended by the manufacturer because the drug passes into breast milk. However, the absolute dose excreted in milk is quite low, and Ultram is generally considered to be acceptable for use in breastfeeding mothers.

The most commonly reported adverse drug reactions with Ultram are nausea, vomiting, sweating and constipation. Drowsiness is reported, although it is less of an issue than for opioids. Patients prescribed tramadol for general pain relief along with other agents have reported uncontrollable withdrawal-like nervous tremors if weaning off the medication happens too quickly. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the seizure threshold. When combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors’ “First Seizure Clinic”, “Tramadol is the most frequently suspected cause of provoked seizures” (Labate 2005). Seizures caused by Ultram are most often tonic-clonic seizures, more commonly known in the past as grand mal seizures. Dosages of coumadin/warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be severe especially in the elderly requiring manual evacuation of the bowel. Furthermore, there are suggestions that chronic opioid administration may induce a state of immune tolerance, although tramadol, in contrast to typical opioids, may enhance immune function. Some have also stressed the negative effects of opioids on cognitive functioning and personality.

Ultram undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to five different metabolites. Of these, M1 (O-Desmethyltramadol) is the most significant since it has 200 times the µ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are excreted by the kidneys. Thus, reduced doses may be used in patients with renal and hepatic impairment.

While the mechanism of action of Ultram is not completely known, it is believed to work through modulation of the noradrenergic and serotonergic systems in addition to its mild agonism of the µ-opioid receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the µ-opioid receptor antagonist naloxone.

Ultram is marketed as a racemic mixture with a weak affinity for the µ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of µ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997).

The serotonergic modulating properties of Ultram mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs) or with use of a light box, since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA-type antagonist effects which have given it a potential application in neuropathic pain states.

Dosage and administration of tramadol for animals: in dogs a starting dosage of 1-2 mg/kg twice a day will be useful for pain management. Cats are administered 2-4 mg/kg twice a day.

When animals are administered tramadol, adverse reactions can occur. The most common are: constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such case, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs. Tramadol should not be co-administered with Deprenyl or any other psychoactive ingredient such as: serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.

Tramadol for animals is one of the most reliable and useful active medications available to veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and monoamine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be utilized for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.