Differences In Transdermal Technology And Pharmacology Of Fentanyl And Buprenorphine

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Because of the difference in construction between both transdermal systems, the reservoir and the matrix composition, one has to be aware of possible side effects of the former. When using the old reservoir system, an additional rate limiting control membrane guarantees a steady stream of the active compound fentanyl into the skin. Contrary, in the matrix composition the active compound is incorporated in a polymer layer (Fig. IV-14). Because of this difference the reservoir system should never be cut in order to reduce the dose or use a damaged system for pain relief. By cutting the fentanyl reservoir patch in half the control membrane will no longer act as a rate limiting lining, which results in leaching of fentanyl and a dose dumping with an increase of opioid being taken up by the skin, with higher plasma level than necessary, resulting in respiratory depression, sedation and/or nausea [34]. In the matrix system, no such dose dumping is initiated whenever the transdermal patch is cut in half. In addition, dose dumping may also be induced by the use of a heating pad [35], a hot shower or heater when being applied over the site of the transdermal patch [36], all of which may result in toxicity with respiratory depression. In addition there have been reports where due to an allergic reaction, a local reactive hyperemia resulted in an increase in reabsorption of fentanyl, which is followed by severe side effects [37, 38]. But most of all there have been a number of reports dealing with the illicit use of fentanyl TTS by drug addicts, since the opioid can be extracted from the reservoir but not from the matrix system. For instance, illicit abuse of fentanyl from the reservoir patch was observed in cases with fatal overdose and with respiratory depression where the resultant dose of 5 mg of fentanyl was scraped from the patch and later injected [39] or heated and inhaled [40]. Overdose with respiratory depression from a transdermal fentanyl (reservoir) patch was also observed in a funeral employee who illicitly removed a patch from a dead body [41], or in a person who misused the patch by placing it into his mouth, which resulted in an increased reabsorption through the mucous membrane of the buccal cavity [42] or by chewing on the transdermal system [43, 44]. In addition, increased reabsorption with respiratory arrest was observed after topical administration of two (reservoir) patches on the well perfused scrotal area [45].

Aside from such scenarios of abuse, care deliverers assisting in the application of fentanyl patches in a nursing home are prone to absorb toxic levels of the drug. This has to be recognized when high doses and a frequent change of patches in elderly patients is necessary and/or the concurrent use of a steroidal spray and cream to decrease skin irritations in patients. This may result in an increase of opioid absorption, predisposing the caregiver to opioid intoxication [46]. The attractiveness of the fentanyl (reservoir) patch for illicit use is not too surprising since a 2.5 mg patch after being used therapeutically for 3 days, still has 0.7-1.22 mg of fentanyl remaining and a 10 mg patch has 4.46-8.44 mg of fentanyl remaining in the disposed patch [47]. Using the pharmacokinetic values of fentanyl with a volume of distribution of 4L/kg and a potential lethal plasma concentration of 3.7^g/L one can calculate the potential lethal dose for a 70 kg person to be 1.036 ^g, a concentration that is well within residual amount of the patch.

The use of this compound is not without problems since fentanyl's potency, as a narcotic has become an abuse challenge among health professionals, including anesthesiologists, physician pharmacists and nurses. By using a transdermal patch, recreational abuse of fentanyl is extremely dangerous due to the low concentration necessary to induce respiratory depression. As the use of transdermal patches within the management of chronic pain increases, therapeutic mis-adventures may be observed. Because of the ease of administration patients may apply more than one patch if they experience a sudden increase in pain. As the patch is capable of delivering higher than necessary doses of fentanyl multiple patches would result in overdose including death [48].

Presently, the new matrix technology, however, results in a much lower incidence of misuse in drug addicts. In fact there is no report in the literature involving the accidental overuse or the misuse of the buprenorphine patch by addicts. This is because the compound is a partial agonist with high receptor affinity, which first results in an antagonist affect at the binding site and only thereafter induces agonist effects at the same site [13, 49]. When taken by an opiate addict such antagonistic capabilities eventually may result in the precipitation or the increase in abstinence symptoms. In addition, buprenorphine is not a drug of choice for addicts, as it does not induce euphoric effects similar to heroin. Compared to morphine and fentanyl the much lower abuse potential of buprenorphine has been demonstrated conclusively by Jasinski and coworkers where the long-term pretreatment with morphine was followed by increasing doses of naloxone. This resulted in increase of abstinence symptoms, while similar intensities were not observed in individuals pretreated with buprenorphine [50, 51]. Last but not least, buprenorphine is fixed in the polymer matrix which practically makes it impossible to set free sufficient amounts of the drug for illicit use. Also, the development of tolerance, often observed after long-term use of pure ^-type ligands like fentanyl, purportedly is not observed with a partial agonist like buprenorphine. The most likely explanation for this difference is the diffrence in intracellular G-protein activation once buprenorphine binds to the receptor. Such a difference protects the binding site from desensitization (i.e. reduction in pharmacodynamic response to the same dose) and there is no need for an increase in doses in order to achieve a similar analgesic level. Since desen-sitization is due to an uncoupling of the binding site from the secondary mediator within the cell, the G-protein, the opioid related message can no longer be transmitted which results in a reduction of clinical efficacy (i.e. analgesia). In contrast, high affinity fentanyl-like ligands result in such an uncoupling, a characteristic trait of ^-type ligands, which is followed by the development of tolerance [52, 53].

Both transdermal patches are indicated for intense cancer pain and other non-malignant related chronic pain with a steady pain level, i.e. phantom pain, post herpetic neuralgia, severe osteoarthritis (OA), rheumatoid arthritis (RA), peripheral neuropathy and/or chronic degenerative back pain.

Recently three low-dose patches of buprenoprhine have been launched (BuTrans® 5, 10, 20 ^g/h; Napp Pharmaceuticals-UK, and Purdue Pharma USA; Fig. IV-20), which specifically are designed for non-malignant pain such as osteoarthritis or chronic low-back pain, when non-opioid analgesics demonstrate insufficient relief.

While age does not affect the extent of absorption from BuTrans® patches, no dose adjustment is needed for the elderly. As with all other transdermal patches the following considerations should be observed when using one of the low-dose opioid patches. BuTrans® is contra-indicated in:

• patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients,

• the treatment of opioid dependence and narcotic withdrawal,

• conditions in which the respiratory center and function are severely impaired or may become so,

• patients who are receiving MAO inhibitors or have taken them within the last 2 weeks,

• patients suffering from myasthenia gravis,

• patients suffering from delirium tremens,

• during pregnancy and lactation.

The following guidelines for approximate dose equivalents are given when converting from a less potent opioid to BuTrans®. However, due to the large interindividual differences between patients they should be used as a guide to estimate a safe starting dose of the new opioid (Table IV-10).

One major prerequisite for the use of a transdermal system is that of a chronic but stable pain level. It is also important to keep in mind that the potential misuse either

Butrans Patch Excipients

Pod of-' release backing layer

Figure IV-20. Structure of the low-dose buprenorphine patch BuTrans®

Pod of-' release backing layer

Figure IV-20. Structure of the low-dose buprenorphine patch BuTrans®

Table IV-10. Approximate dose equivalents when rotating from a less potent oral opioid to the low-dose patch BuTrans®

Oral daily dose

5 ßg/h BuTrans®

10 ßg/h BuTrans®

20 ßg/h BuTrans®

Tramadol

< 30mg/day

50-100 mg/day

100-150 mg/day

Codeine

30-60 mg/day

100-120 mg/day

150-180 mg/day

Dihydrocodeine

> 60 mg/day

> 120mg/day

> 180 mg/day

by foul play, therapeutic misadventure or even assisted suicide may be considered when toxicity associated with the use of transdermal fentanyl or buprenophine is observed.

Both the fentanyl transdermal therapeutic (fentanyl TTS) and the buprenorphine transdermal system (buprenorphine TDS) are the only two non-invasive agents indicated in patients with gastro-intestinal malabsorption or who are unable to swallow

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Responses

  • MAGNUS YOUNG
    What is the difference between fentanyl and butrans?
    3 years ago
  • frankie
    How to get to fentanyl in matrix patch?
    3 years ago
  • Nora
    What is difference between Fentanyl Transdermal system and Buprenorphine transdermal system?
    3 years ago
  • einojuhani
    What is the difference between butrans and butec patches?
    8 months ago
  • Uwe Fink
    What is the difference between matrix and reservoir fentanyl patches?
    4 months ago

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