Prescribed medications for alleviating suffering symptoms in patients receiving palliative care at a tertiary care hospital

Introduction

Palliative care is an interdisciplinary approach to patients with serious illnesses and their family, focusing on improving quality of life through measures including symptom management, quality communication, and assistance navigating complex medical decisions (1). Palliative symptom management addresses not only the physical aspect of suffering symptoms but also the psychological, social, and spiritual dimensions of suffering for total symptom relief (2). High-quality symptom assessment and management are fundamental to providing positive outcomes for palliative care patients and their families (3).

In Thailand, palliative care has been developing since the late 1990s and increasingly received attention from government organizations (4). However, palliative care has not been fully integrated into the Thai public health system and has a limited range of services (5). Furthermore, there is a shortage of palliative care specialists, including physicians, nurses, and pharmacists, particularly in tertiary care government hospitals. Additionally, issues such as drug availability and equitable access to treatment remain problematic. A national survey in 2012 revealed that essential drugs for palliative care, particularly opioids, were not appropriately distributed in Thai government hospitals (6). Concerning hospitalized patients in tertiary care government hospitals in Thailand, nearly 20% were palliative care patients (7). Of these, only 20% received a specialist palliative care consult, and one-quarter of patients with pain were not received analgesics. Thus, improvements in palliative care services are still required with regards to structure and access to opioids (5,8). In addition to pain and dyspnea, there is a lack of information about pharmacological treatment for other suffering symptoms.

Therefore, the objective of this study was to determine the proportion of pharmacological treatment of suffering symptoms and prescribing patterns in hospitalized patients who received palliative care at a tertiary care government general hospital in Thailand. We present this article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-24-52/rc).

Methods

The study was a retrospective descriptive study conducted at Prachuapkhirikhan Hospital; one of the tertiary care government general hospitals in Thailand. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval was obtained from the ethics committee of Prachuapkhirikhan Hospital (No. PKHREC 003/62), and the ethics committee of Faculty of Dentistry and Faculty of Pharmacy, Mahidol University (No. MU-DT/PY-IRB 2019/052.1508). Individual consent for this retrospective analysis was waived.

All patients aged over 18 years old who admitted to the hospital between April 1, 2016, and March 31, 2019, and received palliative care (ICD-10 Z515) as determined by their physician were included in the study. Patients were recruited if they met at least one of the following palliative care screening criteria: (I) patients who experienced a decrease in their activity of daily living by more than 50%, as assessed by Palliative Performance Status (PPS), Karnofsky Performance Score (KPS), or Eastern Cooperative Oncology Group (ECOG); (II) patients with multiple comorbidities; (III) patients in advanced stages of disease, with uncontrollable disease and uncomfortable complication; (IV) terminal delirium; (V) cachexia or continuous weight loss of ≥10% during the previous 6 months, or serum albumin levels consistently below 2.5 mg/dL; (VI) persistent hypercalcemia; (VII) unresponsive to treatment for specific diseases; (VIII) patients and/or their family who decided to discontinue full treatment for specific comorbidities; (IX) patients with frequent unexpected admissions; and (X) patients affected by circumstances such as serious falls, situations of functional loss situations, or hospital admissions. Patients were excluded if they died within 24 hours of admission or if their suffering symptoms and/or treatment of these symptoms were not recorded.

All data were extracted from the patients’ medical charts, including age, sex, primary diagnosis for receiving palliative care, comorbidities, time since palliative care was provided, and suffering symptoms [which included ten physical symptoms (dyspnea; fatigue; constipation; pain; nausea/vomiting; anorexia/cachexia; sleep wake disturbances; diarrhea; delirium; and malignant bowel obstruction), and two psychological symptoms (depression and anxiety)]. All suffering symptoms were identified using the definition of the World Health Organization (WHO). Their respective treatment of each suffering symptom was extracted from the medical charts, including type of medication, dosage regimen, route of administration, and medication adjustment. All prescribed medications and their indications for individual suffering symptoms were recorded in the doctor’s order sheet. However, if not stated in the doctor’s order sheet, the indications could be found in the nurse’ note. Treatment was categorized into two groups: causative treatment and symptomatic treatment. Causative treatment was defined as treatment focused on the underlying cause of each symptom. If the underlying cause could not be indicated, the treatment was classified as symptomatic treatment. Individual data were collected using a code system to prevent identification of individual patients.

Measured outcomes and statistical analysis

The study outcome was the proportion of pharmacological treatment and prescribing patterns for each symptom. The frequency of each suffering symptom, calculated as period prevalence, was also analyzed. Descriptive statistics were employed, and data were expressed as percentages or mean with standard deviation (SD).

Results

The analysis included 296 admission events. The majority of patients were male (55%), with an average age of 67.69±14.77 years. Approximately 67% of patients or their primary caregivers expressed willingness to receive palliative care upon admission (Table 1). The top three primary diseases for which palliative care was sought were cancer (37.16%), cardiovascular disease (21.62%), and infection (18.92%), respectively. A majority of them were admitted to the hospital for the first time following their primary diagnosis. The average hospital stay duration was 14.32±13.43 days, whereas the average duration of palliative care during admission was 9.00±10.54 days. Regarding discharge status, 55.4% died during their admission.

Suffering symptoms were reported in 290 admission events (97.97%), and the frequency of each suffering symptom is presented in Table 2. Dyspnea was the most commonly reported symptom (81.08%), followed by fatigue, constipation, pain, and nausea/vomiting (41.89%, 35.14%, 25.34%, and 11.49%, respectively). Concerning the treatment of suffering symptoms, all patients who complained with fatigue, insomnia, depression, and anxiety received pharmacological treatment (Table 2). Treatment of fatigue focused on correcting underlying causes such as anemia, electrolyte imbalance, and hypoglycemia. Selective serotonin reuptake inhibitors and benzodiazepines were used to treat depression, insomnia, and anxiety. Dyspnea, pain, nausea/vomiting, delirium, and malignant bowel obstruction were treated in at least 80% of each symptom. Remaining suffering symptoms, including constipation, diarrhea, anorexia/cachexia, and sedation, were treated in at least 50% of cases.

Focusing on dyspnea, nearly all patients with dyspnea (n=239, 99.58%) received pharmacological treatment. Of these, 104 admissions (43.51%) receiving treatment for underlying conditions contributing to dyspnea, such as respiratory tract infection, congestive heart failure, ascites, and acute exacerbation of chronic obstructive pulmonary disease. Meanwhile, 135 admissions (56.49%) received symptomatic treatment specifically targeting dyspnea. In terms of the pharmacological treatment pattern for relieving dyspnea, 14.8% received only an as-needed regimen, while 85.2% received around-the-clock (ATC) regimen (Figure 1). Strong opioids, including morphine intravenous infusion (IVIF; 61/135) and midazolam IVIF (21/135), were the most frequent treatments as part of the ATC regimen for dyspnea (45.19%, and 15.56%, respectively). Only 23.7% (32/135) received both the ATC regimen and breakthrough regimen.

Figure 1 Pharmacological treatment pattern for relieving dyspnea (n=135) and medications used as ATC regimen (n=115). ATC, around-the-clock.

For the treatment of pain, there were 71 admissions that received symptomatic treatment, but only 38 admissions (53.5%) recorded pain score using the numerical rating scale before initiating treatment. Most of these cases involved nociceptive type of cancer pain, with 14 cases experiencing moderate pain and 11 cases experiencing severe pain. Only half of the 38 admissions received ATC regimens of analgesics (Figure 2). Among these, the majority (84.2%) received strong opioids which was morphine IVIF or sustained release tablet. Few received adjuvant analgesics predominantly gabapentin and amitriptyline. Focusing on cases with moderate and severe pain, 50% of patients experiencing moderate pain and 15.8% experiencing severe pain still received only as-needed regimen of opioids.

Figure 2 Pharmacological treatment pattern for relieving pain (n=38) and medications used as ATC regimen (n=19). ATC, around-the-clock.

Regarding constipation, it was found that 36 out of 104 cases (34.6%) were caused by opioid use [opioid-induced constipation (OIC)]. Among these, 89% (32 out of 36) received laxatives, predominantly sennosides, magnesium sulfate, and lactulose. Meanwhile, 8.3% (3 out of 36) received ispaghula husk, a bulk-forming laxative.

Discussion

This retrospective study aimed to assess the prevalence of pharmacological treatment for suffering symptoms in patients admitted to inpatient units at Prachuapkhirikhan Hospital who were diagnosed to receive palliative care by their primary physicians. Since there are no palliative care specialist physicians or other healthcare professionals specializing in palliative care in our hospital, treatment related to suffering symptoms is managed by general physicians or specialists in other areas. The characteristics of our patients, including age, primary diagnosis, and suffering symptoms, are consistent with reports from the WHO (9).

Concerning the prevalence of distinct suffering symptoms, dyspnea or shortness of breath was the most common complaint in our study, which differs from previous studies in cancer patients where pain and fatigue are commonly reported (10-14). This variation may be attributed to our focus on patients admitted to inpatient units. Therefore, dyspnea, as a debilitating symptom that significantly impacts patients’ activities of daily living and quality of life (15), was the primary reason for hospital admission in our study. However, following dyspnea, other suffering symptoms such as fatigue, constipation, pain, and nausea/vomiting were also observed, which aligns with findings from other studies.

Tragically, most of our patients received palliative care when they were already in the advanced stages of disease. As a result, more than half of them passing away in the hospital, with an average duration of palliative care of about 9 days. This late implementation of palliative care in our patients led to negative outcomes. Current evidence suggests that early palliative care interventions, ideally initiated at least 6 months before death, in advanced cancer patients are associated with more favorable outcomes compared to late implementation (16-18). Given its significance, there is a need for multidisciplinary collaboration in palliative care between non-palliative care physicians and other healthcare specialists such as nurses or pharmacists. This collaboration should involve structured intervention conversation about palliative care (19-24).

With respect to pharmacological treatment for suffering symptoms, it involves addressing the underlying cause(s) and relieving symptom severity to enhance patient comfort. Fatigue, a complex symptom commonly experienced by advanced cancer patients (25), can result from the disease itself, received treatments, and various chronic physical or psychological comorbid conditions, such as anemia, pain, depression, anxiety, cachexia, sleep disturbance, and immobility. These factors lead to biochemical changes in the body, including increased proinflammatory cytokines, growth factors, circadian rhythm modulation, disruption of the hypothalamic-pituitary-adrenal (HPA) axis, serotonin dysregulation, vagal-afferent activation, anemia, and abnormalities in the generation or utilization of adenosine triphosphate (26,27). In our study, patients presenting with fatigue had their underlying causes identified (anemia, electrolyte imbalance, and hypoglycemia), and all received specific treatment targeting these causes. Additionally, regarding depression and anxiety, all our patients received pharmacological treatment. This is because our physicians are experienced in managing these symptoms and frequently prescribe antidepressants and benzodiazepines in their practice.

Concerning treatment of dyspnea, one patient in our study did not receive any treatment for dyspnea due to refusal of all interventions. Dyspnea can stem from various potential causes, which can be categorized into tumor-related and non-tumor causes. For non-tumor causes, patients received specific treatment targeting these underlying causes, which is the initial step in managing dyspnea. For those whose dyspnea cannot be corrected, oral and parenteral opioids are considered the mainstay of treatment regardless of the cause (28). Opioids act on mu receptors, reducing air hunger discomfort, decreasing spontaneous respiratory drive, and reducing the sensitivity of the central breathing center (29). Effective relief can be achieved with low doses of oral morphine, typically around 10 mg daily. In general, a ceiling effect is typically observed beyond a daily dosage of around 30 mg of oral morphine (30).

In our study, the median dose for ATC regimen of IVIF morphine was 1 mg/hour, equivalent to about 72 mg of oral morphine daily. This dosage may appear higher than recommended, but it is important to note that our patients were in advanced stages of disease and may have been in the end-of-life period. In addition, not all patients with dyspnea received ATC regimens of opioids. A systematic review by Jennings et al. revealed that using 24-hour acting oral or parenteral opioids could significantly improve dyspnea intensity both in the morning and evening (31). Hence, the treatment regimen for dyspnea should ideally include both ATC regimen and as-needed regimen, as found in our study at a rate of 23.7%.

However, some dyspnea patients in our study received benzodiazepines, specifically IVIF midazolam, instead of opioids. The role of benzodiazepines in managing dyspnea remains less clear (32). Benzodiazepines should be considered for dyspnea in the presence of clear concomitant anxiety significantly contributing to the patient’s experience of dyspnea, or after an opioid has undergone a reasonable therapeutic trial (28). Unfortunately, we could not assess the rationale behind the use of benzodiazepines in these scenarios due to the retrospective nature of our chart review study.

Regarding pain management, it is considered that approximately half of the patients who presented with pain did not receive appropriate pain assessments, especially in terms of identifying the type of pain and assessing pain severity at baseline. This issue persists within the palliative care service of government hospital in Thailand (5,7). Each patient should be treated individually, as their pain management may require different dosages and/or interventions to achieve effective symptom relief. Without this essential information, it is impossible to determine the appropriateness of analgesic prescriptions according to the WHO analgesic concept (33,34).

The primary goal of good pain management is to minimize the patient’s pain and the need for breakthrough medication. However, a similar trend was observed in opioid prescribing for dyspnea. Only half of our patients who presented with pain and had baseline pain assessments received the ATC regimen, while the remainder did not. This latter group included patients who complained of nociceptive pain with moderate and severe intensity. These patients should receive their pain medicines throughout the day through an ATC regimen, either via intravenous administration or sustained release preparations. This approach allows for continuous pain relief and minimizes the episodes of pain the patient may suffer throughout a 24-hour period (35).

Indeed, while opioids are effective in managing dyspnea and pain, they are linked with various adverse events, including OIC. OIC can persist throughout the duration of opioid treatment and significantly impact the quality of life for palliative patients. Opioids contribute to constipation by impairing propulsive and peristalsis movements, inhibiting intestinal mucosal secretion, enhancing intestinal fluid absorption, and impairing anal sphincter function (36). As a result, stimulant laxatives and osmotic laxatives are typically recommended as the first-line treatment for OIC. It is important to note that some of our patients received ispaghula husk, a bulk-forming laxative, is not effective for treating OIC (37). It may exacerbate abdominal pain and potentially contribute to bowel obstruction (38). Therefore, clinicians should exercise caution when prescribing bulk-forming laxatives and consider alternative treatments for OIC in palliative care patients receiving opioids. In addition, treatment for constipation was primarily provided when patients experienced symptoms (68 out of 69 cases received laxatives for symptomatic treatment). However, if the constipation was mild, the treatment did not be initiated even if the patient received opioid. This finding reflects actual clinical practice in our setting. Thus, healthcare providers should be mindful in treating and preventing constipation, especially when opioid have been prescribed.

Our study has some limitations. Firstly, the findings are based on a retrospective study conducted at a single tertiary care hospital in Thailand. This could restrict the generalizability of our results to other regions within Thailand, as well as to countries with different healthcare structures. Secondly, some crucial baseline characteristics of our participants are incomplete due to the retrospective chart review study design. These data, especially severity of each suffering symptoms, could offer valuable insights into the medication patterns used to alleviate suffering symptoms in individual patients. Additionally, clinical outcomes after receiving pharmacological treatments could not be evaluated due to incomplete and unsystematic records. Accordingly, a prospective study design with multicenter collaboration would be beneficial. Furthermore, our result can inform the development of hospital policies aimed at enhancing palliative care services, specifically in establishing multidisciplinary healthcare teams for palliative care.

Conclusions

This retrospective study revealed that palliative care in our tertiary care hospital primarily targeted patients with cancer, cardiovascular disease, and infectious disease. Dyspnea emerged as the most frequently reported suffering symptom. While more than 50% of all suffering symptoms received pharmacological treatment, the lack of comprehensive assessment of symptoms severity remained a significant concern.

Acknowledgments

The success of this study is dedicated by the attentive and advice from all authors. Thanks to the officer of Faculty of Pharmacy, Mahidol University for giving consultation of research process. We are also grateful to Prachuapkhirikhan Hospital for permitting us the hospital data for this study.

Funding: This study was supported by research scholarship from Faculty of Pharmacy, Mahidol University, Thailand.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-24-52/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-52/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-52/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (Available at https://apm.amegroups.com/article/view/10.21037/apm-24-52/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Prachuapkhirikhan Hospital (No. PKHREC 003/62), and the ethics committee of Faculty of Dentistry and Faculty of Pharmacy, Mahidol University (No. MU-DT/PY-IRB 2019/052.1508). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Morrison RS, Meier DE. Clinical practice. Palliative care. N Engl J Med 2004;350:2582-90. [Crossref] [PubMed]
2. Kittelson SM, Elie MC, Pennypacker L. Palliative Care Symptom Management. Crit Care Nurs Clin North Am 2015;27:315-39. [Crossref] [PubMed]
3. Henson LA, Maddocks M, Evans C, et al. Palliative Care and the Management of Common Distressing Symptoms in Advanced Cancer: Pain, Breathlessness, Nausea and Vomiting, and Fatigue. J Clin Oncol 2020;38:905-14. [Crossref] [PubMed]
4. Nilmanat K. Palliative care in Thailand: Development and challenges. Can Oncol Nurs J 2016;26:262-4. [PubMed]
5. Chaiviboontham S, Pokpalagon P. Palliative care model in Thailand. Int J Palliat Nurs 2021;27:132-46. [Crossref] [PubMed]
6. Thongkhamcharoen R, Phungrassami T, Atthakul N. Palliative care and essential drug availability: Thailand national survey 2012. J Palliat Med 2013;16:546-50. [Crossref] [PubMed]
7. Pairojkul S, Thongkhamcharoen R, Raksasataya A, et al. Integration of Specialist Palliative Care into Tertiary Hospitals: A Multicenter Point Prevalence Survey from Thailand. Palliat Med Rep 2021;2:272-9. [Crossref] [PubMed]
8. Dokmai P, Meemon N, Paek SC, et al. Structure and process of palliative care provision: a nationwide study of public hospitals in Thailand. BMC Health Serv Res 2021;21:616. [Crossref] [PubMed]
9. Knaul F, Radbruch L, Connor S, et al. Chapter 2: How many adults and children are in need of palliative care worldwide? In: Connor SR. editor. Global Atlas of Palliative Care. 2nd ed. London: Worldwide Hospice and Palliative Care Alliance (WHPCA); 2020:17-32.
10. Harding R, Selman L, Agupio G, et al. The prevalence and burden of symptoms amongst cancer patients attending palliative care in two African countries. Eur J Cancer 2011;47:51-6. [Crossref] [PubMed]
11. Van Lancker A, Velghe A, Van Hecke A, et al. Prevalence of symptoms in older cancer patients receiving palliative care: a systematic review and meta-analysis. J Pain Symptom Manage 2014;47:90-104. [Crossref] [PubMed]
12. Ramsenthaler C, Kane P, Gao W, et al. Prevalence of symptoms in patients with multiple myeloma: a systematic review and meta-analysis. Eur J Haematol 2016;97:416-29. [Crossref] [PubMed]
13. Seow H, Guthrie DM, Stevens T, et al. Trajectory of End-of-Life Pain and Other Physical Symptoms among Cancer Patients Receiving Home Care. Curr Oncol 2021;28:1641-51. [Crossref] [PubMed]
14. Webber K, Davies AN, Leach C, et al. Symptom prevalence and severity in palliative cancer medicine. BMJ Support Palliat Care 2023;13:e270-2. [Crossref] [PubMed]
15. Laviolette L, Laveneziana PERS Research Seminar Faculty. Dyspnoea: a multidimensional and multidisciplinary approach. Eur Respir J 2014;43:1750-62. [Crossref] [PubMed]
16. Bandieri E, Banchelli F, Artioli F, et al. Early versus delayed palliative/supportive care in advanced cancer: an observational study. BMJ Support Palliat Care 2020;10:e32. [Crossref] [PubMed]
17. Seow H, Sutradhar R, Burge F, et al. End-of-life outcomes with or without early palliative care: a propensity score matched, population-based cancer cohort study. BMJ Open 2021;11:e041432. [Crossref] [PubMed]
18. Gonzalez R, Srinivas S, Waterman BL, et al. Impact of early vs late palliative care referrals on healthcare utilization in patients with pancreatic cancer. J Cancer Res Clin Oncol 2023;149:14997-5002. [Crossref] [PubMed]
19. Pini S, Bekker HL, Bennett M, et al. A Structured Intervention to Support Early Palliative Care Conversations for Oncology Patients - A Qualitative Feasibility Study. Clin Oncol (R Coll Radiol) 2022;34:e515-22. [Crossref] [PubMed]
20. Mohammed S, Swami N, Pope A, et al. Strategies used by outpatient oncology nurses to introduce early palliative care: a qualitative study. Cancer Nurs. 2023; [Crossref] [PubMed]
21. Ferrell BR, Temel JS, Temin S, et al. Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:96-112. [Crossref] [PubMed]
22. Vanbutsele G, Van Belle S, De Laat M, et al. The systematic early integration of palliative care into multidisciplinary oncology care in the hospital setting (IPAC), a randomized controlled trial: the study protocol. BMC Health Serv Res 2015;15:554. [Crossref] [PubMed]
23. Chelazzi C, Ripamonti CI. How early should be "Early Integrated Palliative Care"? Support Care Cancer 2023;32:41. [Crossref] [PubMed]
24. Wangnamthip S, Panchoowong S, Donado C, et al. The Effectiveness of Cancer Pain Management in a Tertiary Hospital Outpatient Pain Clinic in Thailand: A Prospective Observational Study. Pain Res Manag 2021;2021:5599023. [Crossref] [PubMed]
25. Potter J. Fatigue experience in advanced cancer: a phenomenological approach. Int J Palliat Nurs 2004;10:15-23. [Crossref] [PubMed]
26. Wang XS. Pathophysiology of cancer-related fatigue. Clin J Oncol Nurs 2008;12:11-20. [Crossref] [PubMed]
27. O'Higgins CM, Brady B, O'Connor B, et al. The pathophysiology of cancer-related fatigue: current controversies. Support Care Cancer 2018;26:3353-64. [Crossref] [PubMed]
28. Crombeen AM, Lilly EJ. Management of dyspnea in palliative care. Curr Oncol 2020;27:142-5. [Crossref] [PubMed]
29. Kwon JH, Kim MJ, Bruera S, et al. Off-Label Medication Use in the Inpatient Palliative Care Unit. J Pain Symptom Manage 2017;54:46-54. [Crossref] [PubMed]
30. Abernethy AP, Currow DC, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ 2003;327:523-8. [Crossref] [PubMed]
31. Jennings AL, Davies AN, Higgins JP, et al. A systematic review of the use of opioids in the management of dyspnoea. Thorax 2002;57:939-44. [Crossref] [PubMed]
32. Kamal AH, Maguire JM, Wheeler JL, et al. Dyspnea review for the palliative care professional: treatment goals and therapeutic options. J Palliat Med 2012;15:106-14. [Crossref] [PubMed]
33. Sholjakova M, Durnev V, Kartalov A, et al. Pain Relief as an Integral Part of the Palliative Care. Open Access Maced J Med Sci 2018;6:739-41. [Crossref] [PubMed]
34. St Marie B. Pain management in patients receiving palliative care. Oncol Nurse Advis 2013;2013:e1-6. [PubMed]
35. Perron V, Schonwetter RS. Assessment and management of pain in palliative care patients. Cancer Control 2001;8:15-24. [Crossref] [PubMed]
36. ALMouaalamy N. Opioid-Induced Constipation in Advanced Cancer Patients. Cureus 2021;13:e14386. [PubMed]
37. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology 2019;156:218-26. [Crossref] [PubMed]
38. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract 2014;2014:141737. [Crossref] [PubMed]