Fentanyl Transdermal

Mechanism of Action

Fentanyl is a synthetic opioid agonist, which acts primarily at the μ-opioid receptor. It is 100 times more potent than morphine resulting in an estimated conversion ratio of 1 to 100 to provide an equal degree of analgesia. Its low molecular weight, high potency, and lipid solubility make it ideal for delivery via the transdermal route. After absorption and entrance into circulation, fentanyl can exert potent effects on areas of the brain that are highly responsible for analgesia. Fentanyl is a 4-anilidopiperidine compound. Like other opiates, this synthetic form exerts its effect by acting as a high-affinity agonist on selective Mu-opioid receptors in the brain. Also, it can exercise its effects on delta and kappa receptors to a lesser degree. The activation of Mu-opioid receptors causes analgesia and stimulating areas of the brain responsible for addictive potential.[4] Fentanyl can be detected in serum after about 1 to 2 hours after first administration but does not reach the therapeutic index until approximately 12 to 16 hours due to the need for fentanyl to saturate the epidermis before more efficient absorption.[5] Matrix patches are designed to deliver fentanyl at a constant rate and are available in various doses: 12, 25, 50, 75, and 100 mcg/hour, requiring replacement every 72 hours. It may require 12 to 24 hours for plasma levels of fentanyl to stabilize after starting patch therapy or changing the dose.

The transdermal route eliminates the first-pass metabolism of fentanyl by the liver, increasing bioavailability to 90%, making it possible to use lower doses of the drug, thus reducing the incidence of adverse effects. Fentanyl metabolism occurs via cytochrome P450 (CYP34A) enzymes into inactive metabolites; hence drugs that enhance or inhibit cytochrome P450 will affect its metabolism.[6] The elimination half-life after patch removal is 13 to 22 hours; this is due to the slow release of fentanyl from the skin depot, as mentioned above. Several studies have shown that when compared to sustained-release oral morphine (SROM), transdermal fentanyl has a 30% lower incidence of adverse effects such as constipation and sedation (p<0.05). Furthermore, randomized, controlled, open-label trials suggest that transdermal fentanyl is safe and as effective as SROM in treating chronic cancer pain.

Administration

The patch has an adhesive side that contains an active ingredient that must be applied directly flat on the skin. The skin should be cleaned with water before application and allowed to dry to be free of oil and other debris.[1] The patch should be applied to intact, clean, and healthy skin. Skin with scars, rashes, or open wounds should be avoided. Areas with excess hair require clipping if applying the patch in that location.[1] The ideal areas to apply the adhesive patch are the chest, back, and arms. The dose will vary depending on the surface area of the patch. Multiple patches may be used at once. Patches must not overlap one another. Patches should not be consecutively be applied one after another in the same location.[1] 

The transdermal fentanyl patch must be removed after 72 hours and replaced with a fresh patch in a new suitable location. The fentanyl will be absorbed first through the topmost layer of the epidermis (stratum corneum) until further reaching the blood vessels to enter the systemic circulation and exert effects on the target receptors. An important consideration with the transdermal patch is the secondary reservoir of the skin. After about 24 hours, significant amounts of fentanyl transfer into the epidermis, which will act as a reservoir for fentanyl; only after the epidermis has absorbed enough drug will it enter the systemic circulation. This action provides a sustained level of fentanyl to avoid inconsistent pain control. This secondary reservoir phenomenon allows for the continual absorption of fentanyl and continues to exert effects on target receptors until the reservoir amount descends below the threshold.[7] In addition to administration, proper disposal is important to avoid intentional abuse and misuse of the discarded patch adhesive by bystanders, children, and healthcare personnel.[8][9]

Adverse Effects

The most common adverse drug reactions of transdermal fentanyl are nausea (incidence of 10 to 90%), vomiting (incidence of 10 to 90%), and constipation.[7] Adverse side effects are manageable with stool softeners and antiemetics.[1] Other less common adverse effects associated with chronic cancer pain include respiratory depression. Transdermal fentanyl originally had an indication for acute postoperative pain, but this is no longer the case. There was a higher incidence of respiratory depression in this subgroup of patients who had not previously been exposed to opioid analgesics and were not opioid-tolerant. Less respiratory depression in cancer patients is suspected due to their previous tolerance of short-acting, non-transdermal forms of opioids, causing tolerance to fentanyl. Also, long term management and time for proper titration of the dose yields improved side effect profiles (excluding constipation). Constipation is a common side effect of opioids, including transdermal fentanyl, and requires management with laxatives. However, patients prescribed transdermal fentanyl reported less constipation than patients treated with oral morphine. Transdermal fentanyl has been shown to cause both hypotension and hypertension in patients with postoperative and chronic pain. Additional adverse effects include rash and erythema at the application site of the patch that abates after removal or with antihistamine therapy. However, the rash is usually not severe enough to remove. Hypoventilation has been noted as an adverse effect.[1] 

As is characteristic of opioids, the withdrawal of transdermal fentanyl may result in additional adverse side effects such as nausea, vomiting, diarrhea, and shivering. These symptoms may occur when decreasing dosage, abrupt cessation of use, or changing to an alternative opioid medication.[1] The chronic pain management indication of transdermal fentanyl allows for the clinician to tailor and titrate to the appropriate dose to minimize adverse effects, improved tolerability, and compliance for the patient.[1]

Contraindications

Contraindications of transdermal fentanyl include use during the acute postoperative pain period for short term pain control, intermittent pain control, or mild pain.[10][11][12] Patients who experience hypoventilation, respiratory compromise (including acute or severe asthma) or respiratory depression may not take transdermal fentanyl.[10][11] Children under the age of 12 or children with a weight of under 50 kgs and who are over 18 should not use this drug.[13] Additionally, patients who are sensitive to fentanyl or other opiates or non-tolerant to opioids should not receive transdermal fentanyl. Due to the administration mechanism, patients who experience sensitivity to adhesive should not use transdermally administered fentanyl and consider other forms of administration.[11]

Monitoring

Fentanyl is an extremely potent opioid and requires monitoring due to the low therapeutic drug concentration. A blood concentration of 0.6 ng/ml to 3.0 ng/ml is appropriate for analgesia. The gold standard method of determining fentanyl concentration for monitoring is Liquid chromatography-mass spectrometry. Alternative methods of monitoring included radioimmunoassay. However, it is known to overestimate concentrations of fentanyl by 29 to 100%. Monitoring Fentanyl is increasingly important when the patient is subject to polypharmacy. Notable drugs to pay special attention to are those which inhibit CYP3A4 metabolism and cause an increase in Fentanyl concentration leading to toxicity. Examples of such medications include azole class antifungals as well as macrolide antibiotics.[13] 

CYP3A4 inducers may also reduce the level of fentanyl to a non-therapeutic level causing the patient inadequate analgesia and distress. Such drugs include rifampin, phenytoin, and carbamazepine.[13] Other medications such as those that fully or partially block Mu opioid receptors (Naloxone and Buprenorphine, respectively) will induce withdrawal as transdermal fentanyl will not be able to exert its effect on Mu opioid receptors.[7] Monitoring proper disposal and screening for misuse within the healthcare industry is especially important for this drug. Fully used transdermal fentanyl patches contain up to 84% of the original dose within the adhesive gel and may be misused by healthcare personnel.[5]

Toxicity

The most concerning adverse reaction with fentanyl is respiratory depression. The treatment approach is by management via mechanical ventilation, using a laryngeal mask airway (LMA), or bag-mask ventilation. Securing the airway is of utmost importance to counteract hypoventilation.[5] Naloxone administration will block mu-opioid receptors in severe cases. However, immediate antagonism of such receptors has the possible outcome of precipitating withdrawal symptoms that merit attention. Symptoms of opioid withdrawal may include nausea, vomiting, piloerection, myalgia, rhinorrhea, photophobia, and autonomic hyperreactivity.[14] Repeat administrations of naloxone may often be required. Also, the transdermal fentanyl patch requires removal, and the area of the skin should be wiped clean. Additional medication from the upper layer of the skin will continue to absorb; however, the remaining amount of the removed patch will be unable to precipitate toxicity.[5]

As mentioned earlier, fentanyl is a synthetic opioid that is 100 times stronger than morphine. Due to its powerful opioid properties, fentanyl diversion for misuse is a problem. Fentanyl is added to heroin to increase its potency or is disguised as highly potent heroin. Many users believe that they are purchasing heroin, but it has been adulterated with fentanyl – which often results in overdose deaths.

Enhancing Healthcare Team Outcomes

Transdermal fentanyl is extremely effective for pain control, but it requires careful monitoring. Physicians, nurses, pharmacists, and allied health professionals (NPs and PAs) must have training in patient safety, possess the proper knowledge and readily available information to screen for opiate abuse, misuse, and toxicity.[15] Healthcare team members recognize signs of addiction, dependence, and adverse side effects. Healthcare professionals who order and administer transdermal fentanyl must be conscious of the specific indications for the drug to avoid non-indicated usage. Proper protocols must be in place and discussed to prevent accidents in administration. To add, every member in contact with chronic pain patients must be knowledgeable on opioid reversal agents. Proper communication and delivery of opioid medications such as transdermal fentanyl must be discussed, and clear communication among all healthcare members involved in patient care should take place to avoid adverse effects. Interprofessional team communication among all healthcare team members will result in more effective outcomes from fentanyl therapy with fewer adverse events. [Level 5]