Frequency of Concomitant Use of Gabapentinoids and Opioids among Patients with Cancer-Related Pain at an Outpatient Palliative Care Clinic

Abstract

Background:

Patients with cancer-related pain use opioids for nociceptive pain, while gabapentinoids are common to treat neuropathic pain. The simultaneous use of opioids with gabapentinoids has been associated with an increased risk of opioid-related death.

Objectives:

Determine the frequency of combined use of gabapentinoids among patients receiving opioids for cancer-related pain. We also examined if concomitant use of opioids and gabapentinoids together was associated with increased scores of fatigue and drowsiness on the Edmonton Symptom Assessment Scale (ESAS) compared to patients on opioids.

Design:

Retrospective study of patients on opioids and opioids plus gabapentinoids at their third visit to the outpatient Supportive Care Center.

Results:

We found that 48% (508/1059) of patients were on opioids. Of these patients, 51% (257/508) were on opioids only, and 49% (251/508) were on opioids plus gabapentinoids. The median (interquartile range [IQR]) morphine equivalent daily dose for patients on opioids was 75 (45, 138) mg, and opioids plus gabapentinoids was 68 (38, 150) mg (p = 0.94). The median (IQR) gabapentinoid equivalent daily dose was 900 (300, 1200) mg. The median (IQR) for ESAS-fatigue in patients on opioids was 5 (3, 7), and opioids plus gabapentinoids was 5 (3, 7) (p = 0.27). The median (IQR) for ESAS-drowsiness in patients on opioids was 3 (0, 5), and opioids plus gabapentinoids was 3 (0, 6) (p = 0.11).

Conclusion:

Almost 50% of advanced cancer patients receiving opioids for pain were exposed to gabapentinoids. Maximal efforts should be made to minimize potential complications from the concomitant use of opioids with gabapentinoids.

Introduction

Many patients with advanced cancer have pain that requires pharmacologic treatment. Moderate-to-severe nociceptive pain is often treated with opioids, while neuropathic pain related to chemotherapy-induced toxicity or physical compression of the nerve is usually treated with a variety of medications, including gabapentin and pregabalin (gabapentinoids).¹

The potential risks associated with the coprescription of opioids with gabapentinoids span somnolence² to unintentional overdose. The drowsiness associated with gabapentinoids is thought of as occurring in the initial days of treatment, after which the patient becomes accustomed to the drug and somnolence improves. Due to case reports of prolonged hypoventilation in postoperative patients receiving gabapentinoids,^3–5 the product monograph was amended to include a warning that respiratory depression may occur when given simultaneously with opioids.² Recent population-based studies report that concomitant use of an opioid and gabapentin⁶ and pregabalin⁷ are associated with a substantial increase in the risk of opioid-related death. Patients with advanced cancer or receiving palliative care were excluded from these studies.

The primary objective of our study was to determine the frequency of the combined use of gabapentinoids among patients receiving opioids for cancer-related pain. The secondary objective was to determine if there was an association between the use of gabapentinoids in patients taking opioids and the severity of self-reported fatigue and drowsiness on the Edmonton Symptom Assessment Scale (ESAS). We also explored the demographic and clinical predictors of concomitant use of opioids with gabapentinoids and compared them with patients only on opioids.

Methods

We conducted a retrospective study approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center. During the study period from February 1, 2015 to December 1, 2017, retrospective data were extracted from chart review by palliative medicine specialists (K.M. and A.H.) and two physicians (A.R.D.M., M.N.) and an advanced practice registered nurse (P.E.), who were trained for chart review for the purposes of this study. Data were collected from the third visit to the outpatient Supportive Care Center.

Patients

The study was aimed at reviewing patients taking opioids either alone or in combination with gabapentinoids. Eligible patients were 18 or older with a diagnosis of local, advanced, or metastatic cancer taking either an opioid or an opioid and gabapentoid concomitantly and had at least three visits to the outpatient Supportive Care Clinic. Patients are referred to the Supportive Care Center for a variety of reasons, all at the discretion of their primary oncologist. Cancer-related pain in the most common reason for referral to our center, and at their first encounter with our team, most patients are taking opioids. Patients whose pain syndrome is not directly related to cancer and patients with pain with no evidence of disease are not treated for pain syndromes at the Supportive Care Center. Patients not taking opioids were not eligible for this study. Data collection from a patient's third visit to the Supportive Care Center was chosen to minimize the different patterns of prescribing opioids and gabapentinoids that may be practiced by the referring medical teams. We presumed that by the third visit to the Supportive Care Center a comprehensive assessment of the patient's pain would have occurred, along with any necessary adjustments of opioids and gabapentinoids. The MD Anderson Supportive and Palliative Care Handbook, 5th edition,⁸ guides the clinical practice and all physicians adhere to the management established within. The use of gabapentinoids is limited to patients who have a clear neuropathic component to their pain syndrome; a suggested titration schedule is provided in the Handbook which recommends initiating gabapentin at “100 mg three times a day, titrated up over 3–5 days to 300 mg three times a day.” Pregabalin is not recommended or used by our clinicians. Due to the concerns of sedation with gabapentin, the Handbook recommends that it “can be titrated up to 3.2 g/day if necessary.”

We reviewed the electronic medical records of randomly selected patients seen in the Supportive Care Center between February 1, 2015 and December 1, 2017. Charts were reviewed in reverse chronological order starting in the year 2017 and then moving to the year 2016 and so on until ∼250 patients for each cohort (opioid alone vs. opioid and gabapentoid) were identified.

For each patient's third clinic visit, the following data were collected: demographics including age, sex, race, cancer type, and cancer stage; ESAS scores; Eastern Cooperative Oncology Group (ECOG) performance status score; Memorial Delirium Assessment Scale (MDAS) score; Edmonton Classification System for Cancer Pain (ECS-CP); Cut-down, Annoyed, Guilty, and Eye-opener (CAGE) score for alcoholism (positivity ≥1/4 in females, ≥2/4 in males); tobacco use (history of and current use); Illicit drug use history; dose of opioid used as morphine equivalent daily dose (MEDD); dose of gabapentoid used expressed as gabapentoid equivalent daily dose (GEDD); the presence of other medications that may cause an increase in fatigue or drowsiness; and the presence of other medications that may cause a decrease in fatigue or drowsiness. Opioid conversions were calculated using the conversion tables of the MD Anderson Supportive Care team, and conversion from pregabalin to gabapentin was calculated using an available conversion factor.⁹ Patients were excluded from the study if any of the data above was missing.

Statistical analysis plan

Data were summarized using standard descriptive statistics such as mean, standard deviation, median, interquartile range (IQR), range for continuous variables; and frequency and proportion for categorical variables. Association between use of opioids only or opioids plus gabapentinoids and categorical demographic and clinical characteristics were examined by chi-squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test was used to assess the differences on continuous variables, such age, MDA, ESAS, and MEDD, between patients using opioid only and patients using opioids plus gabapentinoid. Multivariate linear regression models were applied to test association between gabapentinoid dose and ESAS Fatigue as well as between gabapentinoid dose and ESAS Drowsiness when controlling for MEDD. For the secondary objectives, sample size calculation was performed assuming 20% of patients had a coprescription of an opioid with a gabapentoid, while 60% of patients had opioid alone.

Results

Figure 1 shows patient accrual to the study. We reviewed a total of 1116 patient records. Over the study period, 48% (508/1059) of patients were on opioids. Of these patients, 51% (257/508) were on opioids alone, and 49% (251/508) were on opioids plus gabapentinoids.

FIG. 1.

Patient accrual.

Baseline characteristics of the patients are presented in Table 1. There were no statistically significant differences in the demographic and clinical characteristics, such as age, race, sex, tumor grade, MDAS score, or ECOG score between the two groups.

Table 1.

Demographics and Baseline Characteristics for Patients on Opioids versus Opioids Plus Gabapentinoids

Variable	Opioids only	Opioids plus gabapentinoids	p
Patients, n (%)	257 (51%)	251 (49%)
Median age (IQR)	61 (51, 69)	59 (49, 69)	0.18
Race, n (%)
White	182 (71)	170 (68)	0.62
Black	34 (13)	43 (17)
Hispanic	17 (7)	16 (6)
Other	16 (6)	11 (4)
Asian	8 (3)	11 (4)
Sex, n (%)
Female	154 (60)	137 (55)	0.22
Cancer type, n (%)
Breast	49 (20)	40 (16)
Head and neck	44 (18)	32 (13)
Thoracic	35 (14)	46 (18)
Gastrointestinal	33 (13)	48 (19)
Genitourinary	25 (10)	38 (15)
Gynecological	24 (10)	20 (8)
Other	18 (7)	20 (8)
Hematological	12 (5)	6 (2)
Skin	10 (4)	5 (2)
Neurologic	1 (1)	2 (1)
Tumor grade, n (%)
Metastatic	191 (75)	188 (75)	0.13
Locally advanced	30 (12)	39 (16)
Localized	18 (7)	7 (3)
Recurrent	13 (5)	11 (4)
Other	3 (1)	6 (2)
ECOG, n (%)
0–1	40 (16)	53 (22)	0.22
2	141 (55)	129 (53)
3–4	74 (29)	63 (26)
ECS-CP, n (%)
Nociceptive only	197 (76)	59 (24)	<0.001
Neuropathic only	1 (1)	9 (3)
Mixed nociceptive and neuropathic	59 (23)	183 (73)
MDAS, median (IQR)	1 (0, 2)	1 (0, 2)	0.14

ECOG, Eastern Cooperative Oncology Group; ECS-CP, Edmonton Classification System for Cancer Pain; IQR, interquartile range; MDAS, Memorial Delirium Assessment Scale.

ESAS scores, MEDD, and GEDD for the opioid alone and the opioid plus gabapentinoid groups are presented in Table 2. There was no difference in the MEDD (median, [IQR]) between those patients on opioids alone (75 [45, 138] mg) versus those on opioids plus gabapentinoids (68 [38, 150] mg) (p = 0.94). The median (IQR) gabapentinoid equivalent daily dose was 900 (300, 1200) mg.

Table 2.

Edmonton Symptom Assessment Scale Scores, Morphine Equivalent Daily Doses, and Gabapentinoid Equivalent Daily Doses for Patients on Opioids versus Opioids Plus Gabapentinoids

Variable	Opioids only	Opioids plus gabapentinoids	p
Patients, n (%)	257 (51%)	251 (49%)
ESAS, median (IQR)
Pain	5 (3, 7)	5 (3, 7)	0.06
Fatigue	5 (3, 7)	5 (3, 7)	0.27
Nausea	1 (0, 4)	0 (0, 4)	0.42
Depression	1 (0, 3)	1 (0, 4)	0.39
Anxiety	2 (0, 4)	2 (0, 5)	0.06
Drowsiness	3 (0, 5)	3 (0, 6)	0.11
Shortness of breath	1 (0, 4)	1 (0, 4)	0.67
Appetite	4 (2, 6)	4 (1, 6)	0.51
Feeling of wellbeing	4 (2, 5)	4 (2, 6)	0.53
Sleep	4 (2, 6)	5 (2, 7)	0.31
Financial distress	1 (0, 4)	1 (0, 6)	0.22
Spiritual pain	0 (0, 2)	0 (0, 2)	0.43
Median MEDD, mg, (IQR)	75 (45, 138)	68 (38, 150)	0.94
Median gabapentinoid equivalent daily dose, mg, (IQR)	—	900 (300, 1200)

ESAS, Edmonton Symptom Assessment Scale; MEDD, morphine equivalent daily dose.

There was no difference between the ESAS-fatigue (p = 0.27) or ESAS-drowsiness (p = 0.11), when comparing the opioid alone group to the opioid plus gabapentinoid group. The opioid alone and opioid plus gabapentinoid group had similar percentages of patients (8% and 6%, respectively, p = 0.44) taking methylphenidate, which may mitigate some fatigue and drowsiness. There were no other significant differences in ESAS scores between the two groups.

Multivariate linear regression models were used to determine if ESAS-fatigue and ESAS-drowsiness were associated with GEDD when controlling for the MEDD. ESAS-fatigue (p = 0.92) and ESAS-drowsiness (p = 0.24) were not significantly associated with GEDD when controlling for MEDD.

Discussion

Recent studies document the increased risk of unintentional opioid-related death^6,7 in patients with concomitant prescriptions for opioids and gabapentinoids, and serve to highlight the emerging concern of this particular combination of medications. The simultaneous use of both medications in other patient populations has been documented^10,11 but this is the first to describe its frequency in the cancer-patient population. Although gabapentin and pregabalin are perceived to be safe medications,^12,13 data indicate that they can lead to somnolence¹⁴ and respiratory depression.^3,15,16 We found that approximately half (49% [251/508]) of the patients with cancer-related pain receiving opioids at our clinic were simultaneously receiving gabapentinoids. This represents a high number of individuals that are at risk for delirium, somnolence, and other toxicities due to their underlying comorbidities and often-extensive number of concomitant medications.

There was no association between higher ESAS-fatigue or ESAS-drowsiness scores in the opioid plus gabapentinoid group when compared to the opioid alone group. We also did not find an association between the dose of gabapentinoid and increased ESAS-fatigue or ESAS-drowsiness scores when controlling for the MEDD. Given these findings, it may be reasonable to conclude that the addition of gabapentinoids to opioids did not cause patients to report higher fatigue or drowsiness scores.

Before the late clinical manifestations of central nervous system depression, apnea, and death, patients might self-report higher scores of ESAS-fatigue and ESAS-drowsiness, but we found no such association. One possible reason is that the median MEDD and GEDD were relatively low compared to the population-based studies that found the association between coprescription of opioids and gabapentinoids with increased risk of an opioid-related death.^6,7 Higher doses of opioids and gabapentinoids may indeed cause fatigue, drowsiness, somnolence, apnea, and death, as reported elsewhere. Given the high percentage of patients in our study taking both opioids and gabapentinoids concomitantly, future research examining if there is an increased risk of hospitalization or visits to the Emergency Department is warranted.

Patients taking gabapentinoids did not have a significantly lower MEDD than those taking opioids alone. The fact that the dose of opioids was not significantly different in our two groups suggests that gabapentinoids had a limited role in opioid-sparing in this patient population. In addition to the demonstrated effects of significant sedation and mortality, gabapentinoids have also recently been found to have addictive qualities not dissimilar to opioids, both of which can be associated with nonmedical use.^17–19 There is limited evidence to support the use of gabapentinoids for cancer-related neuropathic pain due to the low quality of published data^20,21 and a lack of efficacy when compared to opioids alone.²² In fact, the clinical practice guideline of the American Society of Clinical Oncology recommends the use of duloxetine over tricyclic antidepressants and gabapentinoids.²³ Given the potential risk of unintentional overdose when gabapentoids are used with opioids, it may be prudent for palliative care physicians to consider alternative medications for the first-line treatment of neuropathic pain in patients with cancer.

There are limitations to our study. First, we only evaluated patients who were referred to the Supportive Care Center. Second, patients may have been prescribed doses of gabapentinoids or opioids that caused high ESAS-fatigue or ESAS-drowsiness before referral to our center. These patients may have been in the midst of dose or medication changes by the Supportive Care team at their third visit. Therefore, their medication regimen may not have been completely aligned with the standards consistent with our group's clinical practice at their third visit. Another limitation to our study is that the study period was before the population-based studies on the risk of concomitant use of opioids with gabapentinoids. It is possible that practice may have changed with the publication of these studies. More research is necessary to better understand if clinical practices changed following the publication of these studies. While we did not find delirium, somnolence, or other toxicities in the patients in our study, it is important to note that we are examining data at a discrete visit to the Supportive Care Center and not longitudinally. More research would potentially clarify the trajectory of side effects that these medications may cause, including whether doses of opioids or gabapentinoids were adjusted before the clinical encounter. Finally, data were collected from a single comprehensive cancer center and may not be generalizable to cancer patients at other institutions.

Conclusions

Almost 50% of advanced cancer patients receiving opioids for pain were exposed to gabapentinoids at a relatively high dose. The MEDD was not significantly lower in those receiving gabapentinoids compared to those not receiving gabapentinoids. While we did not find any associated fatigue and somnolence in our patients, the median dose of gabapentin in our patients is substantially lower than maximal doses. Given the U.S Food and Drug Administration's recent warning about the potentially lethal combination of gabapentinoids and respiratory depression,²⁴ more research is necessary to understand better the risk factors associated with gabapentinoids, fatigue, somnolence, apnea, and death.

Footnotes

Funding Information

No authors involved in this research received any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors Disclosure Statement

Dr. Madden, Dr. Haider, Dr. Rozman De Moraes, Dr. Naqvi, Mrs. Enriquez, Ms. Wu, Mrs. Williams, Mrs. Liu, and Dr. Bruera have no financial disclosures.

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