Introduction
Bortezomib is an effective therapy for patients with multiple myeloma (MM). However, more than one third of patients develop bortezomib-induced peripheral neuropathy (BIPN), requiring dose reduction or treatment interruptions, leading to adverse patient outcomes. 1 - 4 In addition, BIPN can last for years after bortezomib discontinuation and have a significant negative impact on quality of life. 3 BIPN usually presents as both sensory and motor neuropathies, such as paresthesia (tingling, burning sensation), hyperalgesia (increased sensitivity to noxious stimulation) or allodynia (pain that results from a normally innocuous stimulation), distal sensory loss, and reduced deep tendon reflexes. 5 The treatment for BIPN is mainly limited to pharmacological interventions such as opioids, gabapentin, and duloxetine. However, these medications often have limited effectiveness and undesirable adverse effects, 6 - 8 creating the unmet need to explore complementary treatment options.
Acupuncture, a traditional Chinese medical technique in which needles are inserted into certain points on the body, has demonstrated benefits to neuropathic pain in patients with diabetes, 9 cancer, 10 and other conditions. Different acupuncture techniques, for example, auricular acupuncture, have been shown to decrease pain intensity, while more standard reference points for needle insertion have also demonstrated neuropathic symptom improvement in cancer patients. 9 , 11 - 16 Reviews of integrative oncology services at our institution found that approximately one third of the patients receiving acupuncture are treated for peripheral neuropathy, 17 suggesting the need for continued research of its effectiveness.
Our prior single-arm pilot study showed that acupuncture was safe and potentially effective in reducing BIPN-associated pain and improving function, supporting the need for further research. The study focused on the feasibility and safety of acupuncture and reported the overall assessment results as the secondary objective. 11 In this report, through validated Neuropathy Pain Scale (NPS) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) questionnaires, we investigated the effect of acupuncture on individual self-reported BIPN symptoms.
Methods
Patients
Patients with MM who received bortezomib and developed persistent BIPN of grade 2 or higher were eligible for the study; no acupuncture was allowed within 1 month prior to enrollment. The grading system is based on National Cancer Institute Common Toxicity Criteria Adverse Event and defined as follows: grade 1, paresthesias or areflexia without pain or loss of function; grade 2, symptomatic, interferes with function but not daily living activities; grade 3, symptomatic, interferes with daily living activities; and grade 4, sensorimotor neuropathy that significantly interfere with daily living activities. A detailed recruitment plan and exclusion criteria were described in our previous publication. 11 Written consent was provided by each of the 27 patients before enrollment into the clinical trial. The trial was approved by the institutional review board at the University of Maryland and registered at clinicaltrials.gov ( NCT01541644 ).
Interventions
All patients received 10 acupuncture treatments: twice weekly for the first 2 weeks, weekly for 4 weeks, and then biweekly for 4 weeks. The acupuncture treatments were performed by a licensed acupuncturist with 8 years of experience. All acupuncture points were selected for their analgesic characteristics and effectiveness in treating pain, swelling, and numbness (Yin Yang House, 2013). Points included bilateral ear points (Shen men, point zero, and 2 additional auricular acupuncture points where electrodermal signal was detected), bilateral body acupuncture points (LI4, TE5, LI11, ST40), and Ba Feng located in upper and lower extremities were selected, and procedures were described in detail in our previous publication. 11 The de qi, a sense of aching pain, soreness, and heaviness, was achieved in certain acupuncture points (LI4, LI11, and ST40). All patients continued their previously prescribed peripheral neuropathy medications and were encouraged to avoid any changes for the duration of the study.
Peripheral Neuropathy Assessments
Patients were assessed for self-reported signs and symptoms of neuropathy using FACT/GOG-Ntx and NPS. The FACT/GOG-Ntx is an 11-item neurotoxicity subscale to assess patients’ symptoms from neuropathy. The score includes sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. The FACT/GOG-Ntx symptoms include numbness and tingling in the hands (Ntx 1) and feet (Ntx 2), discomfort in the hands (Ntx 3) and feet (Ntx 4), joint pain/muscle cramps (Ntx 5), feeling weak all over (HI 12), trouble hearing (Ntx 6), ringing/buzzing in the ears (Ntx 7), trouble buttoning buttons (Ntx 8), trouble feeling the shape of small objects (Ntx 9), and trouble walking (AN 6). 18 , 19 The sensory subscale includes Ntx1 to 4; the hearing subscale includes Ntx 6 to 7; the motor subscale includes Ntx 5, HI 12, and AN 6; and the dysfunction subscale consists of Ntx 8 to 9. The FACT/GOG-Ntx has been demonstrated as valid, reliable, and sensitive to meaningful clinical distinctions over time. 20 The scores were standardized, the resulting cumulative scores range from 0 to 44, with higher scores indicating less neuropathy.
The NPS is a multidimensional tool with self-reported visual analogue to define pain intensities and associated characteristics. The 10 items of NPS consist of 2 global pain domains (pain intensity and unpleasantness), 6 specific pain qualities (sharp, dull, sensitive, hot, cold, and itchy pain), and 2 spatial qualities (deep and surface pain). 15 With each item scored from 0 to 10, NPS has a cumulative score ranging from 0 to 100. The higher NPS scores indicate worse neuropathic pain symptoms and lower NPS scores indicate less neuropathic pain symptoms.
Both FACT/GOG-Ntx and NPS assessments were administered before the first acupuncture treatment (baseline/week 0), during weeks of 1, 2, 3, 4, 5, 6, 8, and 10 (end of treatment), as well as at 4-week follow-up (week 14).
Data Analysis
Mean FACT/GOG-Ntx and NPS individual item scores were calculated for each week. We used 1-way repeated measures analysis of variance to determine if there were differences in FACT/GOG-Ntx and NPS individual item and domain scores among enrolled subjects over the 14 weeks due to acupuncture treatment. Statistical analyses were conducted using STATA 12 (STATA Corp, College Station, TX). All analyses were 2-sided, with P < .05 indicating significance.
Results
Forty-six MM patients were screened between May 2011 and February 2012. Of 27 eligible patients, all 27 were consented and enrolled in the study ( Table 1 ). The previously published pilot study detailed both patient enrollment and completion. 11 The pharmacological interventions for neuropathy included narcotics (n = 13), gabapentin (n = 12), amitriptyline (n = 3), pregabalin (n = 2), and duloxetine (n = 2). During the study, 22 of the 27 patients remained on the same dose of medication, while 3 patients increased narcotic dosage and 2 decreased.
Table 1.
Baseline Characteristics of the 27 Enrolled Patients (Bao et al 11 ).
Abbreviation: BMI, body mass index.
| Median age | 63 years (range = 49-77) |
| Race, n (%) | |
| Caucasian | 17 (63%) |
| African-American | 9 (33%) |
| Median BMI | 32 (range = 24-49) |
| Peripheral neuropathy grade, n (%) | |
| 2 | 12 (44%) |
| 3 | 14 (52%) |
| 4 | 1 (4%) |
| Acute painful peripheral neuropathy, n (%) | 8 (9%) |
| Median months after drug discontinuation | 19 (range = 1-83) |
| Multiple myeloma status at enrollment, n (%) | |
| Remission | 19 (70%) |
| Progression | 8 (30%) |
The analysis of all 11 items of the FACT/GOG-Ntx demonstrated increasing scores from baseline (week 0) through the end of treatment (week 10) that continued to increase after completion of treatment (week 14; Table 2 ). The higher FACT/GOG-Ntx scores reported at the 4-week posttreatment follow-up (Week 14) indicate a reduction in peripheral neuropathy-associated symptoms as well as an improvement in function. All 4 FACT/GOG-Ntx subscale domains (sensory, motor, hearing, and dysfunction) increased from baseline, during acupuncture treatment, and through posttreatment follow-up at week 14 ( Figure 1 ). The sensory score increased more than 4 points over 14 weeks (5.48 to 9.88, P < .0001), and the motor score also increased from 6.89 to 8.38 ( P = .0001). Hearing and dysfunction scores also increased with statistical significance, indicating improved symptoms. After breaking down each individual symptoms, the mean score of numbness and tingling in hands increased from 1.85 to 2.67 ( P < .0001), and the mean score of numbness and tingling in feet increased from 0.7 at baseline to 2.13 at week 14 ( P < .0001). The discomfort in both hands and feet were lessened with statistical significance. This was more noticeable in foot discomfort, as the mean score increased from 0.81 to 2.25 ( P < .0001). The motor symptoms, including joint pain/muscle cramps and feeling “weak all over,” also increased over time but were not statistically significant ( P = .41 and .26, respectively). A similar trend was observed among the hearing-related symptoms, with higher reported scores for trouble hearing and ringing/buzzing in ears during 10 weeks of acupuncture that remained elevated at week 14, although these were not statistically different from week 0 ( P = .058 and .36, respectively). Dysfunction associated with BIPN, such as trouble with buttons, difficulty with sensing the shape of small objects, and trouble walking all scored higher at week 14, which indicated significant improvement in walking (mean score from 1.67 to 2.5, P < .0001) and buttoning buttons ( P = .0016). These results suggested that acupuncture significantly improved debilitating symptoms associated with BIPN.
Table 2.
Weekly FACT/GOG-Ntx Individual and Subscale Item Averages With Standard Deviations (SD).
Abbreviation: FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. Boldface indicate values (P<0.01), suggesting statistically significant with substantial evidence against the null hypothesis.
| Week 0 Mean (SD) (n = 27) | Week 1 Mean (SD) (n = 18) | Week 2 Mean (SD) (n = 24) | Week 3 Mean (SD) (n = 24) | Week 4 Mean (SD) (n = 23) | Week 5 Mean (SD) (n = 23) | Week 6 Mean (SD) (n = 22) | Week 8 Mean (SD) (n = 21) | Week 10 Mean (SD) (n = 20) | Week 14 Mean (SD) (n = 24) | P | |
| Ntx 1: Hands numbness/tingling | 1.85 (1.46) | 2.06 (0.21) | 2.29 (1.16) | 2.38 (1.21) | 2.57 (1.08) | 2.57 (0.99) | 2.68 (1.04) | 2.52 (1.17) | 2.7 (1.03) | 2.67 (1) | <.0001 |
| Ntx 2: Feet numbness/tingling | 0.7 (1.27) | 1.44 (1.54) | 1.33 (1.24) | 1.58 (1.28) | 1.83 (1.23) | 1.78 (1.2) | 2 (1.27) | 2 (1.05) | 2.05 (1.15) | 2.13 (1.156) | <.0001 |
| Ntx 3: Hands discomfort | 2.11 (1.37) | 2.33 (1.08) | 2.46 (1.14) | 2.38 (1.38) | 2.83 (1.07) | 2.87 (1.06) | 2.86 (1.08) | 2.9 (1.18) | 2.8 (1.06) | 2.83 (1.01) | .0001 |
| Ntx 4: Feet discomfort | 0.81 (1.36) | 1.5 (1.58) | 1.13 (1.12) | 1.71 (1.27) | 2 (1.21) | 1.96 (1.15) | 2.18 (1.05) | 2.14 (1.24) | 2.1 (1.21) | 2.25 (1.29) | <.0001 |
| Ntx 5: Joint pain/muscle cramps | 2.44 (1.15) | 2.67 (1.37) | 2.83 (1.31) | 2.79 (1.35) | 2.91 (1.2) | 3 (1.17) | 3.18 (1.09) | 3.14 (1.01) | 3.1 (1.29) | 2.79 (1.56) | .414 |
| HI 12: Feel weak all over | 2.78 (0.93) | 2.72 (1.02) | 3 (0.88) | 2.13 (0.99) | 3.22 (1.09) | 3.26 (0.92) | 3.41 (0.73) | 3.19 (1.08) | 3.45 (0.76) | 3.08 (1.35) | .2611 |
| Ntx 6: Trouble hearing | 2.96 (1.34) | 3.11 (1.23) | 3 (1.35) | 3.41 (1.06) | 3.26 (1.05) | 3.26 (1.18) | 3.5 (0.96) | 3.29 (1.19) | 3.3 (1.13) | 3.38 (1.01) | .0582 |
| Ntx 7: Ringing/buzzing ears | 3.04 (1.37) | 3.33 (1.33) | 3.13 (1.51) | 3.25 (1.26) | 3.26 (1.36) | 3.39 (1.31) | 3.27 (1.42) | 3.24 (1.45) | 3.25 (1.37) | 3.29 (1.27) | .363 |
| Ntx 8: Trouble with buttons | 2.59 (1.34) | 2.33 (1.49) | 2.63 (1.17) | 2.88 (1.15) | 2.78 (1.24) | 2.78 (1.24) | 2.95 (1.09) | 2.76 (1.22) | 2.75 (1.33) | 2.79 (1.32) | .0016 |
| Ntx 9: Trouble with small shapes | 2.89 (1.37) | 3 (1.14) | 2.67 (1.43) | 2.96 (1.12) | 3 (1.21) | 2.91 (1.2) | 3.09 (1.02) | 2.95 (1.02) | 2.7 (1.34) | 2.92 (1.28) | .3858 |
| AN 6: Trouble walking | 1.67 (1.24) | 1.5 (1.09) | 2.25 (1.07) | 2.33 (1.31) | 2.52 (1.24) | 2.52 (1.12) | 2.59 (1.09) | 2.43 (1.16) | 2.55 (1.05) | 2.5 (1.22) | <.0001 |
| FACT Sensory | 5.48 (4.27) | 7.33 (4.39) | 7.21 (3.79) | 8.04 (4.11) | 9.21 (3.41) | 9.17 (3.62) | 9.73 (3.55) | 9.57 (3.94) | 9.65 (3.84) | 9.88 (3.66) | <.0001 |
| FACT Motor | 6.89 (2.19) | 6.89 (2.74) | 8.08 (2.72) | 8.25 (3.07) | 8.65 (3.02) | 8.78 (2.63) | 9.18 (2.58) | 8.76 (2.79) | 9.1 (2.55) | 8.38 (3.36) | .0001 |
| FACT Hearing | 6 (2.17) | 6.44 (2.15) | 6.13 (2.13) | 6.67 (2.06) | 6.52 (2.17) | 6.65 (2.12) | 6.77 (2.09) | 6.52 (2.36) | 6.55 (2.09) | 6.67 (2.09) | .014 |
| FACT Dysfunction | 5.48 (2.38) | 5.33 (2.63) | 5.29 (2.46) | 5.83 (2.12) | 5.78 (2.29) | 5.69 (2.3) | 6.04 (1.99) | 5.71 (2.12) | 5.45 (2.67) | 5.71 (2.54) | .0378 |
Data collected from the NPS assessment showed consistent, statistically significant score reductions across all 10 items, which indicates reduction in neuropathic pain symptoms after acupuncture treatment. In 6 out of 10 items, the mean NPS score reductions before treatment (week 0) and at posttreatment follow-up (week 14) were greater than 2 points, which is considered a clinically significant change. 15 In particular, the pain intensity score had a mean score reduction of 2.42 points ( P < .0001), from 4.96 at baseline down to 2.54 at week 14. The unpleasant scores also significantly decreased over time from 5.63 to 2.96, with mean score reduction of 2.67 points ( P < .0001). Both score reductions suggested less pain and less unpleasant feeling associated with pain after acupuncture therapy ( Figure 2 ). Among 6 specific pain qualities, hot, cold, sharp, and dull pain were all significantly reduced ( P < .001), with the most significant score reductions observed in hot and sharp sensations ( Figure 2 ). Sensitivity to light touch and itchy pain scores also significantly decreased over time ( P = .001 and .021, respectively). Table 3 displays the NPS individual item scores at each time point during the study.
Table 3.
Weekly NPS Individual Items Averages With Standard Deviations (SD).
Abbreviation: NPS, Neuropathy Pain Scale.
| Week 0 Mean (SD) (n = 27) | Week 1 Mean (SD) (n = 25) | Week 2 Mean (SD) (n = 23) | Week 3 Mean (SD) (n = 25) | Week 4 Mean (SD) (n = 23) | Week 5 Mean (SD) (n = 22) | Week 6 Mean (SD) (n = 23) | Week 8 Mean (SD) (n = 21) | Week 10 Mean (SD) (n = 19) | Week 14 Mean (SD) (n = 24) | P | |
| Q1: Intensity | 4.96 (3.19) | 3.96 (3.26) | 3.43 (2.92) | 3.52 (2.57) | 2.17 (2.29) | 2.64 (2.65) | 2.3 (2.42) | 1.86 (1.85) | 1.95 (2.32) | 2.54 (2.84) | <.0001 |
| Q2: Sharp | 4.56 (3.38) | 3.36 (3.09) | 2.82 (2.98) | 2.56 (2.48) | 2.09 (2.35) | 1.91 (2.37) | 1.96 (2.2) | 1.52 (1.89) | 1.74 (2.56) | 1.67 (2.37) | <.0001 |
| Q3: Hot | 3.48 (3.17) | 2.12 (2.39) | 1.39 (1.77) | 1.48 (2.35) | 1.17 (2.17) | 1.86 (2.73) | 1 (1.83) | 0.9 (1.64) | 1.21 (2.37) | 0.58 (1.25) | <.0001 |
| Q4: Dull | 4.19 (2.89) | 3.04 (2.85) | 2.91 (2.45) | 3.16 (2.76) | 2.09 (1.98) | 2.09 (2.49) | 2.09 (2.15) | 1.9 (1.84) | 1.74 (2.05) | 1.75 (2.19) | <.0001 |
| Q5: Cold | 3.33 (3.24) | 2.2 (2.41) | 2.43 (2.68) | 1.88 (2.49) | 1.83 (2.29) | 1.64 (1.87) | 1.26 (1.79) | 1.48 (2.32) | 1.38 (2.14) | 1.42 (1.93) | <.0001 |
| Q6: Sensitive | 3.44 (3.8) | 2.52 (3.07) | 1.87 (2.65) | 2.16 (2.81) | 2.09 (3.04) | 2.05 (2.77) | 1.61 (2.31) | 1.81 (2.46) | 1.37 (2.19) | 1.79 (2.86) | .0001 |
| Q7: Itchy | 1.44 (2.22) | 0.88 (1.39) | 0.74 (1.36) | 1 (1.68) | 0.96 (1.58) | 0.73 (1.39) | 0.69 (1.36) | 0.71 (1.23) | 0.53 (1.02) | 0.54 (1.22) | .021 |
| Q9: Unpleasant | 5.63 (3.16) | 4.4 (3.06) | 3.83 (2.84) | 3.12 (2.4) | 2.74 (2.51) | 3.09 (2.71) | 2.61 (2.5) | 2.33 (2.24) | 2.32 (2.16) | 2.96 (2.49) | <.0001 |
| Q10a: Deep | 4.96 (3.64) | 3.56 (3.15) | 3.26 (3.03) | 2.96 (2.65) | 2.26 (2.7) | 2.81 (3.09) | 2 (2.61) | 2 (2.02) | 1.68 (2.16) | 3 (3.21) | .0001 |
| Q10b: Surface | 4.96 (3.32) | 3.04 (2.75) | 3.22 (2.61) | 2.16 (1.84) | 2.04 (2.31) | 2.18 (2.3) | 1.69 (1.84) | 2.24 (2.12) | 2.16 (2.25) | 2.04 (2.14) | <.0001 |
Discussion
In this study, we report that acupuncture reduced multiple symptoms associated with BIPN. The self-reported, well-validated FACT/GOG-Ntx and NPS scores were analyzed to delineate which individual BIPN symptoms benefitted the most from acupuncture. The FACT/GOG-Ntx sensory subscale had the lowest score at baseline (indicating the most severe neuropathy symptoms) and the highest score at posttreatment week 14 (indicating the least neuropathy symptoms) with a mean score increase of 4.4 points ( P < .0001). This suggests sensory subscale symptoms may benefit the most from acupuncture. Of the individual symptoms within the sensory subscale, numbness and tingling sensations in both hands and feet and discomfort in feet benefitted the most from acupuncture (all 3 symptoms have P < .0001). With improvement of feet symptoms, the individual symptom score for difficulty walking also significantly increased and improved ( P < .0001). The NPS scores decreased across all 10 evaluated items, indicating acupuncture treatment comprehensively alleviates neuropathic pain symptoms. The most significant reductions were observed in pain intensity, sharp pain, hot pain, unpleasantness of pain, and surface pain.
Our study identified individual symptoms that were alleviated the most by acupuncture. The result confirmed that acupuncture might be beneficial for certain symptoms associated with BIPN. Numbness and tingling in hands and feet, typically debilitating, improved the most along with trouble walking. Other symptoms that significantly improved after acupuncture were pain intensity and both hot and sharp pain sensations. These results could help clinicians recommend acupuncture based on patients’ individual BIPN symptoms.
Notably, our study has the following advantages: acupuncture was the only intervention allowed during the study, and the study did not permit initiating and/or adjusting pharmacological intervention or other interventions like reflexology. The literature suggests that acupuncture in combination with reflexology can reduce both sensory and motor neuropathy equally. 13 However, our study demonstrated that sensory symptoms were alleviated the most with improvement of gross motor symptoms, but not fine motor skills.
There are a few possible explanations to support our findings. Multiple studies have reported that acupuncture can stimulate both Aδ and C fibers, which can be damaged from chemotherapy. 21 - 24 Aδ and C fiber disruption from chemotherapy can cause peripheral neuropathy symptoms such as pain, burning, numbness, and tingling, as well as gait instabilities, weakness, hyperesthesia, allodynia, and dysregulation of temperature discrimination. 23 , 24 Itchiness and unpleasant sensations have been found to also be associated with dysfunction of the same fiber types. 25 Acupuncture can directly suppress diffuse noxious inhibitory controls and lead to activation of Aδ and C fibers and transmission in neurons of the spinal dorsal horn or trigeminal caudalis. 26 Achievement of de qi sensation is a principal of acupuncture that served as the indicator for minimal stimulation level in our study. Studies have suggested that Aδ and C fibers are involved during the de qi sensation and the signal integration into the central nervous system may contribute to the effectiveness of acupuncture for BIPN. 27
Another possible mechanism is through the activation of neurotrophic factors. For example, neurotrophins are important regulators in the development of both the peripheral and central nervous system, 28 and bortezomib can interfere with neurotrophins and prevent nerve growth factor–mediated neuronal survival. 29 Another neurotrophic factor, brain-derived neurotrophic factor (BDNF), has been found to be inversely associated with neuropathic pain in animals. 30 There is evidence to suggest that acupuncture can upregulate BDNF expression and activate BDNF signaling pathways. 31 Further investigations in acupuncture and neuron regulatory factors are warranted to fully elucidate underlying mechanism(s).
The NPS scores have been utilized to analyze the effects of opioids on reducing diabetic neuropathy symptoms, and results showed that oxycodone did not change pain-related pruritus, cold, or sensitive symptoms. 32 In our study, NPS scores acupuncture significantly reduced NPS scores for sensitivity, cold pain, and other pain based on NPS scores. Similar studies also demonstrated the effectiveness of acupuncture but the exact mechanism of action remains unknown. 33 A future randomized control trial comparing opioids and acupuncture could compare the differences between opioids and acupuncture in relieving neuropathic pain and related symptoms.
We would like to acknowledge the limitations of our study. The sample size (n = 27) of the study was small; thus, a larger study is needed to truly understand the impact of acupuncture on peripheral neuropathy symptoms. Additionally, this is a single-arm trial rather than a randomized controlled study, and we could not rule out the placebo effect or regression to the mean effect.
In conclusion, our study provides interesting data suggesting that acupuncture could be particularly beneficial for patients who have BIPN-associated sensory and pain-related symptoms. Further randomized controlled studies are needed to determine the effectiveness of acupuncture to treat BIPN.
Authors’ Note: The funding sources had no involvement in the study design; collection, analysis, and interpretation of data; writing of the report; or decision to submit the article for publication.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by a Memorial Sloan Kettering Cancer Center P30 Grant (P30-CA008748). This study was also funded in part by a R21CA173263 (Ting Bao).
ORCID iDs: W. Iris Zhi https://orcid.org/0000-0003-4263-7272
Evan Ingram https://orcid.org/0000-0002-3019-8455
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