A fixed inhaled nitrous oxide/oxygen mixture as an analgesic for adult cancer patients with breakthrough pain: study protocol for a randomized controlled trial

In 2015, there were approximately 15 million newly diagnosed cancer cases in the world and about 4.3 million new cases in China alone [1, 2]. Cancer pain is common. The estimated prevalence of cancer-related pain is 30–50% for those who are under chronic pain treatment; over 80% of those with advanced disease suffer moderate to severe pain [3]. Most cancer pain is chronic and caused by the tumor. About 50–90% of patients reported intermittent flaring of pain [4] with a 30–40% rate during the early stages of the disease and 70–90% during advanced stages [5].

Cancer pain is classified as background pain or breakthrough pain according to its temporal characteristics [6, 7]. Background pain, also known as chronic persistent pain, refers to a constant or continuous pain that lasts for more than 12 hours per day [6]. Breakthrough pain is a negative prognostic indicator for pain control. The Association for Palliative Medicine of Great Britain and Ireland task group defines breakthrough pain as a transitory increase in pain intensity that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite the use of long-term and around-the-clock analgesics to control background pain. With this definition, breakthrough pain includes both spontaneous (idiopathic) and incidental (precipitated) pain. Spontaneous pain is unpredictable. Incidental pain is somewhat predictable and usually categorized into three sub-types: volitional, non-volitional, and procedural [6‐13]. More than 50% of breakthrough pain is reported to be spontaneous [13].

Both inter-individual and intra-individual breakthrough pain varies in terms of timing and severity [6]. A typical breakthrough pain episode is characterized by a rapid onset (median interval of 3 min to peak pain) [14], moderate to severe in intensity (numerical pain rating scale > 4), short duration (median 30–60 minutes) [14], and self-limited (median number of 4 (times) episodes per day with a range of 1-14) [8, 15]. Patients with breakthrough pain have significantly greater pain-related functional impairment [3, 16] and decreased satisfaction with their analgesic therapy [6]; these are correlated with increased suicidal thoughts [17]. The unrelieved breakthrough pain increases patients’ psychological distress and susceptibility to such illnesses as depression and anxiety [3, 18], which put a negative impact on quality of life [3, 6, 19]. It also lays an additional economic burden on the healthcare system because it increases emergency outpatient visits, hospital admissions, and hospital stay [20‐22].

The World Health Organization three-step analgesia ladder can manage about 80% of background pain with simple interventions [5, 15]. However, the sudden onset, severity, and short duration of breakthrough pain make its management more difficult [15]. Traditionally, breakthrough pain is managed by varying oral immediate-release opioid at 5–15% [23], 10–20% [24], or one-sixth of the total daily opioid dosage [14]. However, in most cases, the pharmacokinetic and pharmacodynamic profiles of such oral opioids do not align with the rapid nature of breakthrough pain [25‐27]. Several studies indicated that the average onset of action for oral opioid (including morphine, oxycodone, and hydromorphone) as rescue medications among hospice patients was greater than 30 min [28, 29]. This long onset of action means that the oral immediate-release opioids are not ideal rescue medications for most breakthrough pain. Studies have evaluated the effectiveness of transmucosal fentanyl formulations for breakthrough pain management [29]. As oral or nasal mucosa allows a more rapid absorption and avoids the first-pass metabolism, transmucosal fentanyl’s onset of action is within 10–15 min after administration [29, 30]. However, some research suggested that the oral transmucosal fentanyl citrate showed a negative correlation with a fixed-schedule opioid regimen and patients have to undergo up to 26 days of the dose-titration phase to determine the optimal dose [31, 32]. Another drawback for this preparation is its high cost. Intravenous morphine is another agent that, at 20% of its basal oral dosage, is a fast, safe, and highly effective option for the relief of breakthrough pain. Its onset of action starts in 3 min and peaks at 10 min [33], but this invasive route of administration and the lack of breakthrough pain management guidelines made this approach less favorable.

A self-administered inhaled nitrous oxide/oxygen mixture is available in pre-prepared cylinders. It has been used in various types of pain management, including labor [34], dental procedures [35], trauma [36], burn dressing [37], surgical procedures, and other medical conditions. The nitrous oxide/oxygen mixture has potent analgesic properties but does not cause loss of consciousness. This gas is safe, noninvasive, and an effective form of pain relief, owing to its low blood/gas solubility ratio, which allows for rapid onset (1–2 min) and short duration of action (35–45 s) after discontinuation [38, 39]. The absorbed gas is also readily excreted unchanged mainly through the lungs [40, 41]. The administration of nitrous oxide/oxygen mixture is easy to control. Its side effects is generally disappear quickly after the termination of exposure to the gas [40, 41].

In mainland China, transmucosal fentanyl preparations are not available and have not been used to control breakthrough pain [data from Chinese Marketed Drugs Database]. According to anesthetists, oral immediate-release opioid is the first choice in controlling breakthrough pain in China. However, with its slow onset of action (20–30 min; peak > 45 min) [42], it delays pain relief and reduces patients’ compliance. Studies by Li et al. showed that a fixed diluted nitrous oxide/oxygen mixture would provide a sufficient analgesic effect during the burn-dressing procedure; patients reported the most satisfaction for this method [17, 37]. However, to our knowledge, there are no studies on the use of nitrous oxide/oxygen mixture to treat breakthrough pain yet. We hypothesize that a nitrous oxide/oxygen mixture can provide the same analgesic effect for cancer patients within breakthrough pain episodes. This is a nurse-led, patient-participate, randomized controlled trial. This article describes the study background, design, treatment administration, and data analysis approach.