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Rapid-Onset Opioids for the Treatment of Breakthrough Cancer Pain: Two Cases of Drug Abuse

Roberta Granata MD, Paolo Bossi MD, Rossella Bertulli MD, Luigi Saita MD
DOI: http://dx.doi.org/10.1111/pme.12382 758-761 First published online: 1 May 2014


Setting In the last few years, the use of opioids for cancer pain has rapidly increased and new molecules have been developed. Currently, rapid-onset opioids are widely used in clinical practice for breakthrough cancer pain (BTcP). However, the tolerability of these molecules is still a matter of debate.

Patients We describe two cases of rapid-onset opioids misuse that have been recently observed at our palliative care unit.

Discussion The reported cases are explicative as they occurred in patients suffering from different types of cancer and with different causes of BTcP. Further investigations are needed to identify factors predicting addiction to this new class of molecules.

  • Rapid-Onset Opioids
  • Abuse
  • Breakthrough Cancer Pain


Moderate and severe pain afflicts approximately 70–80% of patients with advanced cancers [1]. Pharmacologic treatment of cancer pain is now an established clinical practice and is mainly based on opioids. In the last few years, there has been a substantial increase in opioid prescriptions and in the production of new molecules or new pharmaceutical preparations.

The European Association for Palliative Care has recently developed evidence-based recommendations aimed at establishing guidelines for the correct use of opioids in the treatment of cancer pain to make their use easier and safer, minimizing the rate of side effects [1]. Despite this knowledge, cancer pain is undertreated because of numerous barriers [2]. Breakthrough cancer pain (BTcP) is generally considered as a transient increase in pain intensity “breaking through” the background pain, which is adequately controlled with a fixed “around-the-clock” schedule [3]. Episodes of BTcP are observed in 33–65% of patients with chronic cancer pain [4].

The usual approach to BTcP employs a supplementary dose of opioids known as rescue medication.

Recently, there has been a growing interest in the pharmacological treatment of BTcP with rapid-onset opioids because of their pharmacokinetic properties, effectiveness, and safety [5–7].

Specifically, a recent article showed that different transmucosal opioid formulations, such as oral transmucosal fentanyl citrate, fentanyl buccal tablet, intranasal fentanyl spray and most recently, sublingual fentanyl tablet, fentanyl buccal soluble film, and fentanyl pectin nasal spray, provide a rapid effect on BTcP (Table ). These molecules have shown adverse events similar to those of standard opioids [8].

View this table:
Table 1

Commercially available rapid-onset opioids

Oral transmucosal fentanyl citrate20–40 minutes for doses from 200 μgr to 1,600 µgr
Fentanyl buccal tablets35–45 minutes for doses from 100 μgr to 800 µgr
Fentanyl buccal soluble60 minutes for 800 μgr dose
Sublingual fentanyl tablets30–60 minutes for doses from 100 μgr to 800 µgr
Sublingual fentanyl spray0.69–1.25 hours for doses from 100 μgr to 800 µgr
Intranasal fentanyl spray12–15 minutes for doses from 50 μgr to 200 µgr
Fentanyl pectin nasal spray0.33–0.35 hours for doses from 100 μgr to 800 µgr

However, the increased interest in these drugs shall not reduce the attention in identifying patients at risk of rapid-onset abuse or addiction [9,10].

In December 2011, following concerns about misuse, abuse, addiction, overdose, and serious complications due to medication errors, a risk evaluation and mitigation strategy was introduced for all transmucosal immediate-release fentanyl formulations [11].

In the current article, we present two cases of wrong use of rapid-onset opioids, which caused abuse to these drugs. These cases have been observed at our institution and followed by our palliative care unit. In all of these patients, the background pain was adequately controlled with scheduled therapy.

Case Reports

First Case

The first case is about a 23-year-old man diagnosed with a stage T4 N3b undifferentiated nasopharyngeal carcinoma in August 2011.

The patient was treated with induction chemotherapy (docetaxel, cisplatin, and 5-fluorouracil followed by chemoradiation [3 cycles of cisplatin every 3 weeks and radiotherapy total dose 70 Gy in 35 fractions]).

Mucositis was the main adverse event of the treatment, causing also odynophagia. Initially, the patient required paracetamol and codeine for pain management. Subsequently, the medication was switched to oral morphine and transdermal fentanyl patch 25 mcg/h. Because of BTcP episodes when swallowing (mean intensity 8/10 on numerical rating scale), he was instructed to use fentanyl nasal spray before eating, starting with a 100 mcg dose, which was gradually increased to 400 mcg because of low efficacy and concomitant increase of transdermal fentanyl patch to 75 mcg/h for background pain control. With such a therapy, pain was controlled and the patient was able to eat at least with a liquid diet. He was admitted in the hospital for pulmonary infection during the fourth week of radiotherapy and, during his stay, he developed an abnormal behavior. Specifically, he required fentanyl nasal spray more than he really needed and, in case he could not get it, he became restless and aggressive. For this reason, he was followed by our palliative care unit, progressively reducing the amount of rapid-onset opioid till drug stop.

Six weeks after the end of his treatment, after hospital discharge, he was found by his family in a coma status (Glasgow coma scale 7) and he was carried to the emergency department of another hospital, where liquid infusion and artificial respiration were started. After 1 day, he woke up and he started rehabilitation therapy, without residual neurological deficit. According to the discharge letter, the possible cause of this episode may have been coma caused by opioids abuse. This diagnosis was strengthened by the fact that, few days after this episode, the family found out that the patient still used fentanyl nasal spray even if the hospital physicians who had him in charge had stopped to prescribe him this drug.

Second Case

The second case is about a 20-year-old man with an abdominal mass, which was diagnosed at first as a gastrointestinal stromal tumor based on bioptic findings in August 2010. The patient complained of abdominal pain because of the tumor mass, and he was initially treated with oral tramadol 100 mg every 6 hours and ketoprofene 100 mg/day. He started cancer therapy with imatinib but he experienced disease progression, developing liver and peritoneal metastases after 2 months. In consequence, he changed therapy and he was treated with sunitinib for 3 weeks. Despite this therapy, there was further progression of the disease. At the same time, abdominal pain increased with BTcP episodes, so that he could not sleep at night.

He started a new therapy with long-acting oxycodone 10 mg every 8 hours, short-acting oxycodone 5 mg, and fentanyl nasal spray 100 mcg as required (for BTcP).

The patient underwent a new abdominal biopsy and the final diagnosis was a duodenal Ewing sarcoma. The patient started a chemotherapy cycle with vincristine, adriamycin, ciclofosfamide, and ifosfamide for six cycles with a partial response. However, he gradually increased analgesic therapy for background pain to oxycodone 60 mg every 8 hours and gabapentin 200 mg every 8 hours. In the meantime, he required fentanyl nasal spray for BTcP more than he really needed, and he started to use this drug not only for pain control but also for anxiety, nausea, and insomnia. The patient was conscious about the compulsive use of the drug, but he was not able to stop it. In a few weeks, there was a progression of the disease, with a worsening of the abdominal pain. The patient referred a benefit on his pain just with fentanyl nasal spray 400 μgr, and he was finally admitted in the palliative care unit where he died few weeks later.


Rapid-onset opioids for BTcP respond to the needs of drugs with a short-time to analgesic effect. Their main advantages consisted of the fact that they are easily administered and usually well tolerated by patients.

Head-to-head comparison with morphine showed greater pain relief for this class of opioids, mostly because of the rapid onset of effect and paralleled by the short duration, making these drugs effective and reliable [12,13].

Their efficacy led to an increase of their prescription in clinical practice, especially in the oncological setting.

We reported two cases of rapid-onset opioids abuse we observed in 1-year time frame in our tertiary care cancer center. The cases are illustrative as they happened with dissimilar causes inducing BTcP and different types of cancer treated.

Specifically, all two cases were noticed during treatment with fentanyl nasal spray. Moreover, pain was due to cancer in one case and to acute and late side effects of treatment in the other case. Primary diseases were head and neck cancer and Ewing sarcoma, respectively. In all these cases, the background pain was well controlled with scheduled therapy and rapid-onset opioids worked for BTcP, but they caused abuse.

The risk of addiction to opioids was signaled in particular with long-term opioid use and with a low (<10%), even if underscored, prevalence in cancer patients population [14]. The rapidity of drug effect onset could render rapid-onset opioids a class of drug with greater risk of serious complications [10].

There are some issues that must be underscored regarding opioid drug abuse in cancer patients. First, the lack of a clear and uniform definition in this setting of patients could generate different interpretation of a patient behavior. In one survey conducted on experienced pain physicians, it was shown that they did not uniformly evaluate aberrant drug-related behaviors [15]. Moreover, the definitions of addiction and abuse have been developed in a population without medical illness. Secondly, the boundary between addiction, abuse or misuse, and tolerance or physical dependence in cancer patients could be slight. In our case series, we identified the abuse of the drug as abnormal behavior, strong request of the drug in a more frequent manner, compulsive use, and development of anxiety or other symptoms as insomnia or depression.

The use of rapid-onset opioids for BTcP has been increasing and reasonably will grow in the next years. Oncologic patients survive their disease for a longer period of time than years ago, resulting in a longer exposure to opioid treatments. The anticancer therapy itself can cause BTcP as side effect, like in one of the cases we presented. Moreover, it should be underscored that, as result of informative campaigns, physicians have become more aware of how to diagnose and treat BTcP.

Keeping in mind their clinical efficacy, we believe that rapid-onset opioids should be carefully used, and we would suggest registering all assumptions and type of rapid-onset opioids in schedules, checking the correct use.

Currently, there are no conclusive data about possible predictive factors of opioid addiction. Some preliminary evidences showed that previous substance abuse, younger age, and lack of an adequate social and familiar context may be possible factors linked to the predisposition to opioid addiction in oncological patients [16].

In this context, we do need a better risk assessment for opioids misuse, asking the physician to be able to select the most effective drug with lowest risk of side effects. In addition, we should offer alternative treatment other than rapid-onset opioids to patients with a history of substance abuse, and we should pay attention to possible abuse in younger patients or those with a reduced familiar support.

Because of concerns about misuse, abuse, addiction, overdose, and possible serious adverse events related to this class of drugs, a risk evaluation and mitigation strategy for all transmucosal immediate-release fentanyl formulations has been released by the Food and Drug Administration [17].

In consequence, as rapid-onset opioids are extremely effective drugs, on the one hand, we should not fear to prescribe them because of addiction risk and on the other hand, it is of utmost importance being able to detect early the small percentage that could develop serious complications because of the incorrect use of the drug [18].


  • Conflict of Interest: The material of this report has not been previously published and is not currently under consideration for publication in another journal.


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