Optimal treatment of opioid induced constipation in daily clinical practice – an observational study

Patients who were prescribed opioids by their oncologist at an academic hospital and a large teaching hospital over a six month period in 2014 were included in the retrospective study. Data concerning baseline characteristics, opioid and laxative use, and the occurrence of OIC were extracted from the patient charts. When multiple opioid prescriptions were made in the study period, the prescription with the highest oral morphine equivalent daily dose (MEDD) was used for this analysis. Conversion rates from buprenorphine, fentanyl, subcutaneous morphine, oxycodone and tramadol to oral morphine were 2.29, 2.4, 3, 3, and 0.2, respectively [16]. For methadone conversion rates to oral morphine were 4 for doses < 22.5 mg, 6 for doses between 22.5 and 50 mg, and 8 for doses > 50 mg [16]. Notes on the patient’s laxation pattern in the period between 30 days before and after the selected opioid prescription were extracted to evaluate if OIC had occurred. Admittances for OIC were registered for the year prior to and following the selected opioid prescription. In order not to miss admittances with OIC as an underlying cause, we reviewed each admission for the mentioning of (opioid-induced) constipation as a underlying cause for the reason of admission. Constipation was defined as a reported change in laxation frequency to less than 3 stools per week. Due to the retrospective nature of this part of the study, subjective components to constipation could not be assessed. Constipation was considered as opioid induced if this was made explicit in the patient chart, and/or if there was no other major contributing factor specified (e.g. dehydration, obstruction of the GI-tract by a tumor or carcinomatous peritonitis, or side effects from other drugs).

Most of the presented data are descriptive. It was expected that, even despite prophylactic laxative use, patients using fentanyl would have a lower incidence rate of OIC than patients using oxycodone [5]; 10% of the patients using fentanyl would develop OIC, compared to 30% of the patients using oxycodone. In a population in which 40% used fentanyl and 25% oxycodone, a study sample with at least 120 patients using fentanyl and 80 using oxycodone was needed to have 90% power to detect the hypothesized difference in the incidence of OIC between fentanyl and oxycodone (P < 0.05 was considered statistically significant). Descriptive data are presented by their mean or median, and SD or inter quartile range (IQR). Comparisons were made with a Pearson’s Χ² test or Mann-Whitney U test, as considered appropriate. For assessing the effect of multiple factors, multiple logistic regression was used.

The methods of the observational trial to determine the differences in the effect of methylnaltrexone on OIC induced by different opioid subtypes are published elsewhere [5]. Briefly summarized, patients with OIC caused by morphine, oxycodone, or fentanyl, without contra-indications for methylnaltrexone, received a 14-day treatment with methylnaltrexone subcutaneously (SQ) every other day. In this period a laxation diary was kept to monitor the effect of methylnaltrexone. The Bowel Function Index questionnaire (BFI) [17] was completed at the start and end of this treatment period. We aimed to include 78 patients in the oxycodone group, 78 patients in the morphine group and 39 patients in the fentanyl group. This study was approved by the Medical research Ethics Committee of the VU University medical center and performed in accordance with the Helsinki Declaration of the World Medical Association.

The BFI consists of three questions about symptoms of constipation experienced during the past week. Answers to these questions are rated on a scale from 0 to 100 and the final score is calculated by the mean of the three answers. A decrease of 12 points or more between start and end of the study is thought to be a clinically significant response [5, 17].

Data of both studies were anonymized and stored in the web based database system Open Clinica (Open Clinica version 3.3). Statistical analyses were performed with IBM SPSS version 22.0 (IBM, Armonk, NY, USA).

Three hundred twenty seven patients were included in the retrospective analysis. Characteristics of these patients are presented in Table 1. Fentanyl (N = 131, 40%) and oxycodone (N = 90, 28%) were the most frequently prescribed opioid subtypes. Ninety-four patients (29%) did not use a maintenance opioid, only rescue doses. Tumor types, treatment intention (curative or palliative), intake failure (especially reduced fluid intake), and abdominal innervation problems (paralysis of the intestines) between the fentanyl and oxycodone group were significantly different. For fentanyl maintenance treatment continuous-release patches were used. These were mostly prescribed for patients treated with chemo-radiotherapy for head and neck cancer, which explains most differences in characteristics between the treatment groups. When correcting for this tumor type, only intake failure remained statistically significant more frequent in the patients using fentanyl patches (28/95 vs. 8/85 in the oxycodone group, P = 0.001), and abdominal innervation problems were more frequent in the oxycodone group (7/85 vs. 1/95 in the fentanyl group, P = 0.017).

Sixty percent of the patients used concurrent laxatives, mostly a polyethylene-glycol solution (PEG), magnesium oxide, and/or enema’s (55, 7, and 6% respectively, Table 2). Thirty-one patients (9%) used two or more types of laxatives. There were no statistically significant differences in the number of patients using a specific laxative, nor in the dose of laxatives, between patients using fentanyl or oxycodone, except for the dose of magnesium which was higher in patients using oxycodone (N = 5) than in patients using fentanyl (N = 13) (median 6 vs. 3 tablets per day, P = 0.033).

For 257 patients (79%) the attending physician made a note in the patient’s chart on their laxation pattern. Sixty-eight patients (21%) were constipated, of whom 39 (12%) were considered to be constipated due to opioids (Table 3). OIC was equally prevalent in patients treated with oxycodone or fentanyl (12 of 81 pts. vs. 18 of 110 pts., RR 0.9, 95% CI 0.4–2.0). Although there was a statistically significant difference in the oral morphine equivalent daily dose (MEDD) of regularly taken opioids between patients using fentanyl and oxycodone at opioid prescription (fentanyl MEDD 60 mg (IQR 29–120), oxycodone MEDD 40 mg (IQR 40–80), P = 0.006), the difference in the MEDD at diagnosis of OIC was not statistically significant (fentanyl 89 mg (IQR 60–180) vs. oxycodone 40 mg (IQR 40–80), P = 0.231). When analyzing the effects of opioid subtypes fentanyl and oxycodone and MEDD on OIC in a multiple logistic analysis, none showed statistical significance (OR for the risk at OIC for MEDD 0.997 (95% CI 0.990–1.005); for fentanyl 1.310 (95% CI 0.351–4.892); and for oxycodone 4.086 (95% CI 0.630–26.495)). Also, no difference in OIC was found between patients using oxycodone or fentanyl as rescue opioid (13% vs. 9%, P = 0.554).

In the majority of the patients with OIC, the opioid dose remained stable (N = 14) or was increased (N = 14). In 32 patients diagnosed with OIC (82%) the laxative treatment was adjusted, mostly by prescribing a new laxative (N = 20). The main reason not to alter the laxative treatment while a patient was diagnosed with OIC, or to even stop the laxative treatment, was that the patient had entered the terminal phase and was not able to take oral medication anymore (N = 6).

Twenty-two individual patients (7%) were admitted to the hospital for OIC (Table 3). The median MEDD at admission was 70 mg (IQR 40–180). Eleven patients used fentanyl, with a median MEDD of 180 mg (IQR 60–180). Five patients used oxycodone, with a median MEDD of 60 mg (IQR 40–140). The difference between the doses of fentanyl and oxycodone at admission was not statistically significant (P = 0.145). The opioid prescription was adjusted because of OIC in 4 of the 22 patients; in one patient the dose was lowered, in three patients an opioid rotation was performed.

Patients admitted for OIC were mostly treated with enema’s (N = 16) and a 4-l polyethylene glycol solution (N = 11). Complete resolution of constipation was seen with enema’s (N = 5/16), methylnaltrexone SQ (N = 2/5) and with a 4-l polyethylene glycol solution (N = 2/2).

Twenty-six patients were included in the methylnaltrexone trial between July 2012 and December 2015. Baseline characteristics of the included patients are presented in Table 4. Sixteen patients used oxycodone, eight fentanyl and two morphine. Three patients were lost to follow-up because the laxation diary was not returned (two in the fentanyl group, one in the oxycodone group). Of the 23 patients who returned response data of at least one dose of SQ methylnaltrexone, 11 met the primary endpoint of at least 2 laxation responses out of the first 4 doses. These were 8 patients in the oxycodone group (8 of 15 pts., 53%), 2 in the fentanyl group (2 of 6 pts., 33%) and 1 in the morphine group (1 of 2 pts., 50%). Reasons to prematurely stop SQ methylnaltrexone treatment were: per patient request (N = 4), adverse events (N = 2: 1 diarrhea, 1 abdominal pain), intercurrent illness (N = 1), death due to disease progression (N = 1), and unknown (N = 1).