Abstract
Objective
To evaluate acupuncture as a nonpharmacologic intervention for pain management in patients undergoing hematopoietic stem cell transplantation (HSCT).
Methods
Adult patients with multiple myeloma undergoing high-dose melphalan chemotherapy and autologous peripheral blood HSCT were randomized to receive either true (TA) or sham acupuncture (SA) once daily for five days starting on the day after chemotherapy. Use of pain medications and pain scores were assessed at baseline and at days 5, 15, and 30 after transplantation.
Results
Among 60 evaluable subjects, the SA group (vs TA) had greater than five times odds of increasing pain medication use from baseline. Among patients who were opioid nonusers at baseline, all 15 patients in the TA group remained free from opioid use at the end of the study. In contrast, 20% of those in the SA group (four of the 20 patients) started to use opioids after chemotherapy and stem cell infusion (day 5) and 40% (eight of the 20) had become opioid users by day 30 after HSCT (Fisher exact test P = 0.006). Among patients who were taking opioids at baseline, 14% in the TA group vs 10% in the SA group increased opioid intake at day 5, and 21% (TA) vs 30% (SA) at day 30 (P = 0.86).
Conclusions
Acupuncture appears to significantly reduce the need for pain medications during HSCT and the number of post-HSCT opioid users among baseline opioid nonusers. It warrants further studies as an opioid-sparing intervention for pain in HSCT patients.
Keywords: Pain Management, Acupuncture, Opioids, Cancer Pain
Introduction
Among patients with cancer, pain is one of the most common, burdensome, and feared symptoms. A recent meta-analysis of 122 studies (N = 4,199) showed that about 55% of patients experience pain during cancer treatment, with 40% experiencing pain after curative treatment [1]. Pain management for cancer patients includes pharmacologic and nonpharmacologic interventions [2]. Nonpharmacologic interventions are an important part of a comprehensive multidisciplinary pain management plan [1,3,4]. More options in nonpharmacologic pain management need to be explored, and this need has become especially urgent in light of the current opioid crisis. Exposure to opioids during treatment for acute pain is a strong risk factor for patients to become long-term opioid users, even when acute pain has subsided and opioids are no longer appropriate [5]. Better management of acute pain using nonpharmacologic interventions may lead to less chronic opioid use. The Joint Commission, Centers for Disease Control and Prevention, Food and Drug Administration, American College of Physicians, and American Society of Clinical Oncology all recommend incorporating nonpharmacologic interventions to manage pain.
Acupuncture is a nonpharmacologic pain management intervention during which filiform needles are inserted into certain points on the body, followed by hand manipulation, heat, or electrical stimulation to elicit therapeutic effects. Neuroscience research has shown that acupuncture increases production of endogenous analgesic neurotransmitters, such as endorphins and adenosine [6–11]. A systematic review of 17 trials (N = 2,027) conducted for the development of the American College of Physicians practice guidelines showed that acupuncture reduced the intensity of both acute and chronic low back pain more than sham acupuncture [12]. On the other hand, whether acupuncture can prevent acute pain associated with cancer treatment and lead to long-term benefit has not been studied.
Autologous hematopoietic stem cell transplantation (auto-HSCT) can be a curative treatment for multiple myeloma (MM), Hodgkin disease (HD), and non-Hodgkin lymphoma (NHL). Patients receive a single dose of high-dose chemotherapy followed by an infusion of hematopoietic stem cells two days later. Pain is rated one of the top five symptoms during this treatment [13]. Oral mucositis from high-dose chemotherapy is the main source of severe acute pain and the main reason patients are initiated on opioids. Between 30% and 43% of the patients experience severe (grade 3 or 4) mucositis, which creates distress and interferes with eating and drinking. Mucositis pain follows a rather predictable course: It usually starts shortly after conditioning chemotherapy and peaks around day 5 after stem cell infusion, begins subsiding around days 10–15, and has usually resolved by day 30. The pain leads to periods of malnutrition, dehydration, weight loss, depression, and impaired quality of life [14–17]. Oral care and use of filgrastim (G-CSF) help shorten the duration of mucositis, yet opioids remain the mainstay for pain control [18].
We conducted a randomized, sham acupuncture–controlled pilot study in 63 MM patients undergoing auto-HSCT [19]. We found that patients who received sham acupuncture were five times more likely to increase pain medications from baseline than those who received true acupuncture (odds ratio = 5.31, 95% confidence interval = 1.35–20.93, P = 0.017) [19]. Here we report further analysis of which type of patient appeared to benefit the most in terms of reduced pain medication use and which type of pain medication (opioids vs anticonvulsant) was increased. In this population, patients were usually prescribed opioids (most often oxycodone) for management of somatic pain and anticonvulsants (gabapentin or pregabalin) for neuropathic pain. Some patients were taking pain medications before HSCT, whereas others were not. Those who were nonusers at baseline had no significant pain before treatment, and any increase in pain medication use was likely due to pain induced by conditioning chemotherapy and HSCT. To our knowledge, this is the first study evaluating acupuncture’s effect on symptom burden and use of pain medications in this study population.
Methods
Study Design
We carried out a randomized, sham-controlled acupuncture trial between May 2013 and January 2016 at Memorial Sloan Kettering Cancer Center (MSK). Study subjects and evaluators were blinded to group assignment. The Institutional Review Board at MSK approved the clinical trial protocol. The study was registered at ClinicalTrials.gov before subject enrollment.
Study Subjects
Patients diagnosed with multiple myeloma and scheduled for auto-HSCT at MSK were evaluated for eligibility. Those eligible were approached for informed consent. Inclusion criteria were adult multiple myeloma patients (age 21 or above) who were scheduled to receive high-dose melphalan chemotherapy then autologous peripheral blood HSCT. Exclusion criteria were neutropenia (absolute neutrophil count <200/μL, higher risk of infection), thrombocytopenia (platelet count <20,000/μL, higher risk of bleeding), and acupuncture treatment within four weeks before day 1 (residual effects from acupuncture).
Randomization
Randomization was conducted using MSK’s Clinical Research Database system. Patients were randomized to true or sham acupuncture using blocks of randomly permuted length. Randomization was stratified to whether the HSCT was done as inpatient or outpatient.
Intervention
High-dose chemotherapy was given to study subjects on day −2 and stem cell infusion on day 0. True or sham acupuncture was started on day −1, the day after chemotherapy, and continued for a total of five days or until the patient became neutropenic or thrombocytopenic, whichever was sooner. Sham acupuncture was delivered on the same schedule. Every patient received the same pre- and post-transplantation usual care as other HSCT patients who were not in the study, irrespective of group assignment.
Acupuncture is available in both inpatient and outpatient settings at MSK. Licensed acupuncturists who were MSK employees delivered acupuncture treatments once a day in the patient’s hospital room for patients receiving inpatient transplantation or at the clinic for those receiving outpatient transplantation. Each treatment lasted 20 minutes. Acupuncture points in the study protocol were selected according to published data from previous studies in the literature and consensus among the acupuncturists. The acupuncture points were bilateral PC6, ST36, KI3, SP6, LR3, HT7, and Ear Shen Men, and GV20 and Ex-HN3 at midline. SERIN 36-gauge × 40 mm and 40-gauge × 30 mm acupuncture needles were used. The needles were not stimulated by electricity or heat.
We used a previously a validated method to provide sham acupuncture, at the same frequency and duration as true acupuncture [20,21]. An empty plastic acupuncture needle guide tube was tapped on an area near each acupuncture point to generate some discernible sensation. An acupuncture needle was then taped flat on the skin with a piece of adhesive tape for 20 minutes. All study patients wore eye patches during the interventions to prevent them from seeing what the acupuncturist did during the treatment procedure.
Evaluation
Pain scores were evaluated by using the MD Anderson Symptom Inventory (MDASI) [22]. The MDASI is a multisymptom patient-reported outcome (PRO) instrument, validated for multiple myeloma patients and HSCT patients [23]. Study subjects underwent baseline assessment one to two weeks before conditioning chemotherapy, then every day from day −2 to day 5 during the transplantation period (stem cell infusion was at day 0). They were reassessed post-transplantation at around day 15 (the first follow-up visit) and around day 30 (the second follow-up visit). Name and daily dosage of pain medications used by study subjects were recorded in the hospital record. Data from baseline, and days 5, 15, and 30 were extracted. Patients were monitored for adverse events daily during the transplantation period, and then at the first and second follow-up visits.
Masking
Study subjects were blinded to treatment allocation; so were the HSCT team, who were responsible for prescribing pain medications, and research personnel, who were responsible for outcome assessments. Only the acupuncturists were aware of a patient’s group assignment. At the end of the study, patients were asked to guess to which group they were assigned in order for us to evaluate the effectiveness of blinding.
Data Analyses
If a study subject provided both baseline and day 5 assessments, she or he was deemed evaluable for study outcomes. Patients’ data were analyzed according to randomization allocation irrespective of how many treatments they received. We used Stata 12 (StataCorp, College Station, TX, USA) to perform all data analyses. Differences in numbers and proportions of patients who used a specific class of pain medications were analyzed using the Fisher exact test. All analyses were two-sided, with P < 0.05 indicating significance. Average MDASI pain scores and standard deviation were assessed at baseline and at days 5, 15, and 30 after HSCT. Pain score was analyzed as a continuous variable. We used the Student t test to obtain the difference in pain score between the two treatment groups at different time points.
Results
Figure 1 shows the flow of study participants in the trial. Among the 63 randomized patients, two in the true acupuncture group withdrew consent before receiving any intervention and one in the sham acupuncture group received sham acupuncture yet withdrew consent before assessment of the primary end point. Among the 60 evaluable patients, 29 were from the true acupuncture group and 31 were from the sham acupuncture group. The true and sham acupuncture groups were well matched in patient characteristics. Masking was excellent, with about an equal number of patients in each group who guessed that they had received true acupuncture [19].
Figure 1.
Patient flow diagram.
We found that patients in the sham acupuncture group were five times more likely to increase pain medication use from baseline than those in the true acupuncture group [19]. We investigated further which patients had the largest effect size and which class of pain medication was more likely to be used.
We found the differences in increased pain medication use were more prominent among patients who were not on any pain medications at baseline. Among these baseline nonusers, defined as those whose home medication list did not include any pain medication, none in the true acupuncture group used pain medication 30 days after HSCT, whereas 44% in the sham acupuncture group started using pain medication (P = 0.01) (Table 1, last column).
Table 1.
Number and proportion of pain medication users during and after HSCT among baseline nonusers
| Baseline | Day 5 | Day 15 | Day 30 | |
|---|---|---|---|---|
| No. (%) | No. (%) | No. (%) | No. (%) | |
| True acupuncture (N = 12) | 0 (0) | 0 (0) | 1 (8) | 0 (0) |
| Sham acupuncture (N = 18) | 0 (0) | 4 (22) | 4 (22) | 8 (44) |
| P value | – | 0.13 | 0.62 | 0.01 |
HSCT = hematopoietic stem cell transplantation.
We then looked at the use of opioids vs anticonvulsants and found that the reduction of pain medication use could be attributed mainly to prevention of opioid use. Fifteen of 29 patients in the true acupuncture group and 20 of 31 patients in the sham acupuncture group were not opioid users at baseline. Among them, all participants from the true acupuncture group remained nonusers at day 5, whereas four (20%) in the sham acupuncture group became opioid users by day 5 (P = 0.119). At day 15, one (7%) in the true acupuncture group and three (15%) in the sham acupuncture group were using opioids (P = 0.619). By day 30, none in the true acupuncture group were opioid users, whereas eight (40%) in the sham acupuncture group became opioid users (P = 0.006) (Figure 2a). For patients who already used opioids before HSCT, similar proportions of patients from each group had to increase use of opioids (Figure 2b), with no between-group differences.
Figure 2.
Percentage of patients increasing opioid use in the sham group vs true acupuncture (AC) group.
We then looked at patients who were or were not on anticonvulsants at baseline before HSCT. For patients who didn’t use anticonvulsants (some were also opioids users), more patients started to use anticonvulsants after HSCT, although the differences were not significant (Table 2a). For the few patients who were anticonvulsant users at baseline, none in the acupuncture group increased anticonvulsant use, whereas 33% in the sham acupuncture group increased their dose of anticonvulsants (Table 2b).
Table 2.
Number and proportion of anticonvulsant users
| Baseline | Day 5 | Day 15 | Day 30 | |
|---|---|---|---|---|
| No. (%) | No. (%) | No. (%) | No. (%) | |
| a. Baseline nonusers who started using anticonvulsants during and after HSCT | ||||
| True acupuncture (N = 23) | 0 (0) | 0 (0) | 1 (8) | 1 (4) |
| Sham acupuncture (N = 25) | 0 (0) | 4 (16) | 4 (16) | 4 (16) |
| P value | – | 0.11 | 0.11 | 0.35 |
| b. Baseline users who increased anticonvulsant use during and after HSCT | ||||
| True acupuncture (N = 6) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Sham acupuncture (N = 6) | 0 (0) | 2 (33) | 2 (33) | 2 (33) |
| P value | – | 0.11 | 0.32 | 0.32 |
HSCT = hematopoietic stem cell transplantation.
We also evaluated pain scores throughout the course of HSCT. True acupuncture reduced pain scores from baseline (SD) by 1.63 (3.20) on day 5, 1.34 (2.61) on day 15, and 1.45 (2.26) on day 30. Sham acupuncture reduced pain scores to a lesser degree (SD) by 1.10 (2.52) on day 5, 0.80 (3.39) on day 15, and 1.17 (2.93) on day 30 (Figure 3). There were no between-group differences.
Figure 3.
MD Anderson Symptom Inventory pain score during and after hematopoietic stem cell transplantation.
Discussion
Pain management in cancer patients is challenging. During cancer treatment, some patients require strong analgesics including opioids for adequate control of pain, such as that of mucositis during chemotherapy and radiation, or postoperative pain after surgical resection of cancer. However, continuous opioid use after cancer treatment in patients with no active cancer is undesirable. As exposure to opioids during treatment for acute pain is a strong risk factor for patients to become long-term opioid users even when the acute pain has subsided and opioids are no longer appropriate [5], control of acute pain by nonpharmacologic interventions may lead to reduced opioid use after cancer treatment. This would have a significant impact on clinical practice.
In this randomized controlled study of acupuncture, we found that patients who received true acupuncture during HSCT are significantly less likely to require more pain medication during and after HSCT than those who received sham acupuncture. This difference primarily occurred in patients who were not on pain medications before HSCT and was more prominently related to opioid use. Among patients who were opioid nonusers at baseline, 20% (four of 20) in the sham acupuncture group compared with 0% in the true acupuncture group started to use opioids after chemotherapy and stem cell infusion (day 5). Similarly, 40% in the sham acupuncture group compared with about 0% in the true acupuncture group were using opioids after HSCT treatment had been completed (day 30).
Our findings suggest that acupuncture appears to suppress the severity of acute pain after high-dose conditioning chemotherapy so that patients do not experience high pain scores or require opioids (day 5). Those who were not taking opioids at baseline appeared to derive more analgesic benefit from acupuncture than those who were already taking opioids. There could be three possible explanations for this observation. First, acupuncture has been shown to increase endogenous opioid production in animal studies [5,9]. In the absence of exogenous opioids, patients may be more sensitive to the analgesic effect of any increase in endogenous opioids. Second, exogenous opioids may compete with binding of endogenous opioids, thereby limiting the effectiveness of acupuncture. Third, patients who were already taking opioids may have a lower pain threshold. To them, the analgesic effect of acupuncture may not be as strong as that of additional opioids. These possibilities need to be answered by other studies.
Although acupuncture was provided only during the first five days of HSCT, it was associated with reductions in long-term opioid use on day 30, long after acute pain subsided. This raises the possibility that controlling acute pain with a nonopioid intervention may reduce initial exposure to opioids, thus reducing the likelihood of patients using opioids for future pains.
MM patients may also experience neuropathic pain from previous chemotherapy, for example, bortezomib. This is usually treated with anticonvulsants (gabapentin or pregabalin). For unknown reasons, HSCT appears to bring up or worsen neuropathic pain in some of those patients. We observed a small difference between the groups in number of patients who had to start or increase their dose of anticonvulsants (Table 2). The event rate is too low to show statistical significance.
The main weaknesses of our study are 1) small sample size, 2) that our post hoc subgroup analysis needs to be interpreted with caution for false discovery, 3) no long-term follow-up, and 4) lack of nonacupuncture (usual care) controls. The study was not powered to generate definitive efficacy data with reduction of pain medication as the primary end point. It was designed as a study to generate preliminary data for hypothesis generation. The purpose of post hoc analysis is to guide the design of a fully powered larger trial in the future. Most acupuncture studies with sham acupuncture and nonacupuncture (usual care control) have shown a larger effect size when true acupuncture is compared with usual care than when it is compared with sham acupuncture. If we had had a usual care control group, we would have expected to observe a larger effect size. The strengths of the study are 1) a randomized, sham-controlled design, with nonspecific placebo effect accounted for, 2) that our sham acupuncture technique produced excellent masking, and 3) low attrition rate and virtually no loss to follow-up. Based on these findings, we plan to conduct a large randomized controlled trial to generate definitive data on the effectiveness of acupuncture in this setting. If confirmed in a more rigorous study, we could expand pain management options with a drug-sparing, especially opioid-sparing, intervention, that when implemented in the early stages of cancer treatment could reduce opioid requirements for acute pain, thus helping to reduce chronic opioid use after cancer treatment. Such findings could have significant clinical practice implications in reducing unnecessary opioid use among cancer survivors.
Authors’ Contributions
Yi Chan, Matthew Weitzman, Theresa Affuso (acupuncturists); Khaula Malik, Kelsi Clement, Jeremy Taylor, Mollie McMahon, Janice DeRito (research study assistants); and Andrew Vickers, PhD (biostatistician) took part in delivering the interventions, collecting the data, and guiding data analysis, and Ingrid Haviland and Christina Seluzicki helped in preparing and submitting the manuscript. They were partially supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.
Funding sources: This work was supported by a Gateway for Cancer Research grant and the MSK Translational Research and Integrative Medicine Grant; also, by National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant P30 CA008748, the AC Israel Foundation, and the Byrne Fund.
Disclaimer: The study principal investigators were solely responsible for the design and conduct of the study, independent from the funders.
Conflicts of interest: GD received honoraria from Helsinn Healthcare. SG received research funding from Amgen, Actinuum, Celgene, Johnson & Johnson, Miltenyi, and Takeda and served on advisory boards for Amgen, Actinuum, Celgene, Johnson & Johnson, Jazz Pharmaceutical, Takeda, Novartis, Kite, and Spectrum. HL received research funding from Takeda and served on advisory boards for Janssen, Karyopharm, Celgene, and Takeda. The other authors have nothing to disclose.
Ethical approval: This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center. All procedures performed were in accordance with the ethical standards of the institutional research committee. Informed consent was obtained from all individual participants included in the study.
Trial registration: This study is registered at ClinicalTrials.gov as NCT01811862.
References
- 1. Sheinfeld Gorin S, Krebs P, Badr H, et al. Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. J Clin Oncol 2012;30(5):539–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Paice JA, Portenoy R, Lacchetti C, et al. Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34(27):3325–45. [DOI] [PubMed] [Google Scholar]
- 3. Syrjala KL, Donaldson GW, Davis MW, Kippes ME, Carr JE.. Relaxation and imagery and cognitive-behavioral training reduce pain during cancer treatment: A controlled clinical trial. Pain 1995;63(2):189–98. [DOI] [PubMed] [Google Scholar]
- 4. Syrjala KL, Cummings C, Donaldson GW.. Hypnosis or cognitive behavioral training for the reduction of pain and nausea during cancer treatment: A controlled clinical trial. Pain 1992;48(2):137–46. [DOI] [PubMed] [Google Scholar]
- 5. Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD.. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: The role of opioid prescription. Clin J Pain 2014;30(7):557–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Liao HY, Hsieh CL, Huang CP, Lin YW.. Electroacupuncture attenuates induction of inflammatory pain by regulating opioid and adenosine pathways in mice. Sci Rep 2017;7(1):15679.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sawynok J. Adenosine receptor targets for pain. Neuroscience 2016;338:1–18. [DOI] [PubMed] [Google Scholar]
- 8. Otti A, Noll-Hussong M.. Acupuncture-induced pain relief and the human brain's default mode network - an extended view of central effects of acupuncture analgesia. Forsch Komplementmed 2012;19(4):197–201. [DOI] [PubMed] [Google Scholar]
- 9. Wang SM, Kain ZN, White P.. Acupuncture analgesia: I. The scientific basis. Anesth Analg 2008;106(2):602–10. [DOI] [PubMed] [Google Scholar]
- 10. Kaptchuk TJ. Acupuncture: Theory, efficacy, and practice. Ann Intern Med 2002;136(5):374–83. [DOI] [PubMed] [Google Scholar]
- 11. Clement-Jones V, McLoughlin L, Tomlin S, Besser GM, Rees LH, Wen HL.. Increased beta-endorphin but not met-enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain. Lancet 1980;2(8201):946–9. [DOI] [PubMed] [Google Scholar]
- 12. Chou R, Deyo R, Friedly J, et al. Nonpharmacologic therapies for low back pain: A systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017;166(7):493–505. [DOI] [PubMed] [Google Scholar]
- 13. Wang XS, Shi Q, Shah ND, et al. Inflammatory markers and development of symptom burden in patients with multiple myeloma during autologous stem cell transplantation. Clin Cancer Res 2014;20(5):1366–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Cheng KK, Leung SF, Liang RH, Tai JW, Yeung RM, Thompson DR.. Severe oral mucositis associated with cancer therapy: Impact on oral functional status and quality of life. Support Care Cancer 2010;18(11):1477–85. [DOI] [PubMed] [Google Scholar]
- 15. Raber-Durlacher JE, Barasch A, Peterson DE, Lalla RV, Schubert MM, Fibbe WE.. Oral complications and management considerations in patients treated with high-dose chemotherapy. Support Cancer Ther 2004;1(4):219–29. [DOI] [PubMed] [Google Scholar]
- 16. Kushner JA, Lawrence HP, Shoval I, et al. Development and validation of a Patient-Reported Oral Mucositis Symptom (PROMS) scale. J Can Dent Assoc 2008;74(1):59–59j. [PubMed] [Google Scholar]
- 17. Cheng KK. Oral mucositis and quality of life of Hong Kong Chinese patients with cancer therapy. Eur J Oncol Nurs 2007;11(1):36–42. [DOI] [PubMed] [Google Scholar]
- 18. Kashiwazaki H, Matsushita T, Sugita J, et al. A comparison of oral mucositis in allogeneic hematopoietic stem cell transplantation between conventional and reduced-intensity regimens. Support Care Cancer 2012;20(5):933–9. [DOI] [PubMed] [Google Scholar]
- 19. Deng G, Giralt S, Chung DJ, et al. Acupuncture for reduction of symptom burden in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation: A randomized sham-controlled trial. Support Care Cancer 2018;26(2):657–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Lao L, Bergman S, Hamilton GR, Langenberg P, Berman B.. Evaluation of acupuncture for pain control after oral surgery: A placebo-controlled trial. Arch Otolaryngol Head Neck Surg 1999;125(5):567–72. [DOI] [PubMed] [Google Scholar]
- 21. Lao L, Bergman S, Langenberg P, Wong RH, Berman B.. Efficacy of Chinese acupuncture on postoperative oral surgery pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79(4):423–8. [DOI] [PubMed] [Google Scholar]
- 22. Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: The M.D. Anderson Symptom Inventory. Cancer 2000;89(7):1634–46. [DOI] [PubMed] [Google Scholar]
- 23. Jones D, Vichaya EG, Wang XS, et al. Validation of the M. D. Anderson Symptom Inventory multiple myeloma module. J Hematol Oncol 2013;6:13.. [DOI] [PMC free article] [PubMed] [Google Scholar]