We described a case of iatrogenic opioid dependence induced by inadequate fentanyl use for chronic non-cancer pain. The patient was successfully detoxified by sustained-released tramadol without severe withdrawal symptoms.
Iatrogenic opioid dependence is a serious adverse effect associated with long-term opioid therapy for chronic non-cancer pain [1, 7]. In order to prevent its development, it is critically important for the physician to prescribe opioids appropriately. Specifically, since high-dose opioid prescription is one of the major risk factors, the Japanese clinical practice guideline recommends the maximum daily opioid dose as 120 mg of MME [5]. In addition, sublingual formulation of fentanyl can be used to achieve a rapid onset of action, which may enhance abuse potential [8]. Accordingly, it is only indicated for breakthrough pain in opioid-treated cancer patients. In our case, however, the patient treated his chronic low back pain with transdermal fentanyl 6 mg (180 mg of MME) in combination with sublingual fentanyl tablets. This inappropriate opioid use may be a consequence of complicated circumstances, such as patient misinterpretation, patient-physician miscommunication, inadequate physician attitudes towards opioids, and lack of drug monitoring systems.
Inadequate pain management led to drug-seeking behaviors that resemble those seen with opioid addiction. This phenomenon is referred to as pseudoaddiction [9, 10]. In clinical settings, pseudoaddiction can be distinguished from opioid dependence in that the behaviors disappear after appropriate pain treatment. On the other hand, opioid tolerance develops with repeated opioid exposure, resulting in a decrease in the analgesic effect [10, 11]. The development of opioid tolerance has been reported to lead to an increase in opioid consumption and the risk of addiction. Opioid switching or rotation is the process of substituting one opioid for another for improvement of opioid responsiveness [11]. In our case, despite an opioid switching from transdermal fentanyl to equi-analgesic dose of oral morphine, no significant pain relief was observed. Furthermore, his pain intensity did not exacerbate during fentanyl detoxification, even presented a slight improvement over time (Fig. 2), indicating that the occurrence of pseudoaddiction could be excluded.
A crucial first step in the treatment of opioid dependency is detoxification [12, 13]. Opioid detoxification is the supervised withdrawal from causative opioid to minimize withdrawal symptoms. Currently, two types of Food and Drug Administration (FDA)-approved medications, oral methadone and sublingual buprenorphine, are widely used as the standard agents for medical opioid detoxification [12, 13]. Methadone is a full opioid agonist with long half-life and high affinity at the μ-opioid receptor, which can ameliorate the euphoria effects and withdrawal symptoms [14]. Buprenorphine is a partial opioid agonist, which makes it an advantageous alternative to methadone due to its relatively safe profile [15]. Evidence shows that both medications help patients to reach a stabilized physical condition, which then allows them to successfully go through counseling and rehabilitation programs [12,13,14,15]. However, they are not currently prescribed in Japan, i.e., oral methadone is only indicated for the treatment of cancer pain, and sublingual formulation of buprenorphine has not been available yet.
Tramadol is a centrally acting analgesic for treatment of moderate to severe pain in both cancer and non-cancer patients [16]. Since it binds to μ-opioid receptors, tramadol could relieve opioid withdrawal symptoms [17]. In fact, a previous clinical trial showed that oral treatment of immediate-release tramadol (200 or 400 mg) reduces opioid withdrawal in morphine-maintained adults [18]. Another report further demonstrated that the extended-release tramadol of therapeutic dose (200 mg daily) was more efficacious than placebo and supra-therapeutic dose (600 mg daily) in treating withdrawal in opioid dependence patients [19]. In contrast, a recent randomized controlled trial showed that higher doses of extended-release tramadol (up to 600 mg daily) suppressed opioid withdrawal symptom comparably to buprenorphine [20]. Therefore, relatively small dose regimen (up to 300 mg daily) may explain why some withdrawal symptoms were developed in our case.
On the other hand, the affinity of tramadol for the μ-opioid receptor is very low, i.e., 6000-fold less than that of morphine [16]. It may be associated with less incidence of side effects, including lower rates of respiratory depression and reduced abuse liability, compared to other μ-opioid analgesics. Specifically, compared with immediate-release formulations, sustained-release tramadol could provide a more controlled, safe, and prolonged analgesic effect, minimizing adverse effects associated with uncontrolled drugs peak plasma levels [21]. Furthermore, tramadol inhibits the neuronal re-uptake of noradrenaline and serotonin, which contributes to better analgesic effects for chronic pain via activation of descending inhibitory pathways [16, 21]. These pharmacological profiles, along with our case, suggest that the medication with sustained-release tramadol could be an effective alternative approach for supervised opioid detoxification in patients with chronic non-cancer pain. Nevertheless, several important questions remain such as long-term effectiveness and optimal dose regimen. In addition, a Cochrane database systemic review published in 2018 reported that there were insufficient data to determine whether tramadol differs from methadone in alleviating withdrawal symptoms [17]. Therefore, further clinical studies regarding our hypothesis are necessary and warranted.
