Abstract
Objective. This is a case series reporting safety and degree of response to 1 dose level of sweet bee venom pharmacopuncture (SBVP) or melittin as a symptom-control therapy for chemotherapy-induced peripheral neuropathy (CIPN). Setting. All treatments were conducted at the East West Cancer Center (EWCC), Dunsan Oriental Hospital, Daejeon University, Republic of Korea, an institution that uses complementary therapies for cancer patients. Methods. Five consecutive patients with CIPN were referred to the EWCC from March 20, 2010, to April 10, 2010. Patients with World Health Organization Chemotherapy-Induced Peripheral Neuropathy (WHO CIPN) grade 2 or more were treated with SBVP for 3 treatment sessions over a 1-week period. Measures of efficacy and safety. Validated Visual Analog System (VAS) pain scale, WHO CIPN grade, and Functional Assessment of Cancer Therapy–General (FACT-G) were compared before and after the 1-week course of treatment. To ensure the safety of SBVP, pretreatment skin response tests were given to patients to avoid any potential anaphylactic adverse effects. All patients were closely examined for any allergenic responses following each treatment session. Results. One patient discontinued treatment after the first session, and 4 patients completed all treatment sessions. Using each patient as their own comparator, marked improvements of VAS, WHO CIPN grade, and physical section scores of FACT-G were seen in 3 patients. Most important, there were no related adverse side effects found. Conclusion. This safety results of the SBVP therapy merits further investigations in a larger size trial for it to develop into a potential intervention for managing CIPN symptoms. This study will be extended to a dose–response evaluation to further establish safety and response, prior to a randomized trial.
Keywords
Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) involving sensory and motor nerve damage or dysfunction is a common and serious clinical problem that affects many patients receiving cancer treatment. 1 CIPN is often a dose-limiting side effect of several cytotoxic agents, including Vinca alkaloids, platinum analogues, and taxanes. 2 Severe CIPN has been reported in about 5% of patients treated with single agents and up to 38% for those treated with multiple chemotherapeutic agents. 3 Affected patients frequently complain of pain in their extremities and may have signs of paresthesia, hyperesthesia, impaired vibration and joint position sensation, ataxia, myalgia, and muscle weakness. Few patients fully recover but instead continue to experience symptoms and compromised quality of life. 4
There is no standard treatment protocol for the prevention, mitigation, or management of CIPN. There are few effective pharmacological options to treat CIPN symptoms. Analgesics (ie, opioids and nonsteroidal anti-inflammatory agents) are only moderately effective in treating symptoms of neuropathy. Tricyclic antidepressants (eg, nortriptyline and amitriptyline) have also been suggested as therapeutic options for neuropathy. However, there data are minimal to support their uses for CIPN. 5 There are nonpharmacologic approaches to treat CIPN. One study on CIPN reports acupuncture to be a promising treatment with no related adverse side effects. 4 Therapy is often idiosyncratic and individualized, since there are no clinical trials that show any one intervention to be better than another.
Bee venom (BV) therapy has been used as part of Korean medicine from ancient times.6-8 As such, it is not an experimental intervention in Korean culture but does require a scientific investigation to determine its safety and effectiveness. BV acupuncture involves injection of the purified and diluted BV into acupuncture points. Laboratory studies of BV have been carried out in Korea with increasing scientific interest in the role of neuropeptides for treating pain and inflammation. The anti-inflammatory and analgesic effects of BV have been demonstrated in various kinds of animal arthritic models9,10 and in humans.11,12
Sweet bee venom pharmacopuncture (SBVP) therapy uses melittin, a peptide extracted from sweet bee venom. Melittin is the pharmacological component in SBV that inhibits inflammation. 13 It is a low-molecular-weight peptide composed of 26 amino acids, with a molecular weight of 2840. Melittin is reported to have analgesic, anti-inflammatory, and anticancer effects.14-17 In addition, it is a safer product than whole bee venom since the allergenic components and histamine are removed.14-16 One team of scientists carried out a rodent experiment to investigate SBVP safety, finding no mortalities or adverse side effects. 18 The data also support its consistency, quality, and stability. 19 Accordingly, we report our study on the preliminary safety and efficacy of combination acupuncture and melittin injection for CIPN with a small set of data collected as part of routine clinical practice that we treat as a prospective case study. 14
Materials and Methods
Subject Rights and Welfare
This report is a prospective audit of safety and symptom control. As all data were collected as a part of routine clinical practice as a case series, investigational review board application was not filed. Patients who visited the East-West Cancer Center (EWCC), Dunsan Oriental Hospital, Daejeon University, Republic of Korea, from March 20, 2010, to April 10, 2010, with presence of CIPN symptoms were given SBVP treatments. All treatments were conducted with patient consent. Full explanations of the treatment procedure, its unclear efficacy, the small potential for allergic adverse effects, and pain at the site of injection were given according to our institutional policy.
Safety Precautions and Assessment
Patients with major systemic illnesses accompanied by symptoms that required other forms of intervention were excluded. Although we believe melittin is safer than the whole bee venom, patients with a history of allergic reactions were also excluded. Bee venom skin tests were administered to those who met the inclusion criteria to reduce any possible adverse allergic reactions. Clinicians were directed to pay special attention to safety issues, and all patients were questioned and closely examined for any allergic responses following each treatment session.
Patient Characteristics
The sample comprises 5 patients who visited EWCC from March 20, 2010, to April 10, 2010, with presence of CIPN symptoms including pain, numbness, and tingling in the hands or feet (with or without motor dysfunction) after having gone through chemotherapy for at least 28 days. All patients were female with age ranging from 48 to 55 years. The patients had advanced gynecological cancers (ovarian cancer and cervical cancer), which were previously treated with taxol, carboplatin, or paclitaxel. Three patients had World Health Organization (WHO) CIPN grade 2, and 2 patients had WHO CIPN grade 3 symptoms (WHO grading system: grade 0, no symptoms; grade 1, paresthesie and/or decreased tendon reflexes; grade II; severe paresthesie and/or mild weakness; grade III, intolerable paresthesie and/or marked motor loss; and grade IV, paralysis). Their Visual Analog System (VAS) pain levels ranged from 7 to 10, with 0 being no pain and 10 the most excruciating pain. Patient characteristics are shown in Table 1.
Patient Characteristics and Outcome Results of VAS, WHO CIPN Grade, and FACT-G Scores
Abbreviations: VAS, Visual Analogue Scale; WHO CIPN, World Health Organization Chemotherapy-Induced Peripheral Neuropathy grade; FACT-G, Functional Assessment of Cancer Therapy–General; CA, cancer; Tx, treatment; SBVP, sweet bee venom pharmacopuncture.
Treatment Method
The Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) 2010 recommendation guidelines were followed to report the treatment conducted. 20
In the study, a technique called pharmacopuncture, which is a combination of acupuncture and melittin injection, was used. Pharmacopuncture involves the injection of pharmaceutical derivatives (often from natural products) into acupuncture points that are connected to the symptom locations, as defined by Korean medicine. Our treatment approach was based on a previous encouraging case study of acupuncture treatment for CIPN, which reported a successful case series of 5 CIPN patients treated with acupuncture. 4 SBV has been reported to be effective for neurodegenerative diseases associated with microglial activation and other inflammatory symptoms. 21 Through SBVP treatment synergistic effectiveness has been anticipated.
The acupuncture points of Ba Feng and Ba Xie were chosen based on the traditional Korean medicine theories of meridians and a previous acupuncture study on CIPN, which used these same points to relieve pain and numbness for CIPN. 4 Ba Xie and Ba Feng acupoints are located on the extremities of the hands and feet proximal to the margins of the webs between all 5 fingers and toes. Symptoms in the upper extremities were treated with Ba Xie on the hands (8 points bilateral), and symptoms in the lower extremities were treated with Ba Feng points on the feet (8 points bilateral). Patients with symptoms in both upper and lower limbs were treated with Ba Xie and Ba Feng (16 points in total).
Melittin of 0.1 mg/mL concentration was refined and prepared in an aseptic room at the Korean Pharmacopuncture Institute. The concentration was derived from laboratory pharmacological data based on previous clinical experiments on safety. 22 Higher doses can initially cause more pain at the injection site. Sterilized disposable syringe needles (26 G½; 0.45 mm × 13 mm) were used. The depth of SBVP injection was 0.1 cm. The volume of SBVP for each acupuncture point was 0.1 mL.
Three treatments of SBVP over a 1-week period were given, with a 1-day interval between treatments. The actual treatment procedure took no more than 10 minutes as it was a series of quick epidermal injections. The SBVP treatments were performed by a certified oriental medicine doctor with more than 3 years of clinical experience.
Efficacy Assessment
Patient-reported VAS, WHO CIPN grade, and Functional Assessment of Cancer Therapy–General (FACT-G) scores were observed before and after the completion of all 3 SBVP treatment sessions. The VAS scale is a validated method for the assessment of pain used as a measure of treatment efficacy. 23 A score of 0 represents absence of pain and/or discomfort, whereas a score of 10 indicates the worst pain imaginable. The WHO CIPN grade scale has been used to assess symptoms and functions of patients in many published CIPN studies.1,24 Five grades are used, with grade 0 indicating no symptom and grade 4 representing the presence of paralysis. The FACT-G questionnaire (4th edition) was used to evaluate the quality of life of cancer patients. FACT-G comprises 27 specific questions in 4 sections, physical, social/family, emotional, and functional domains, to comprehensively evaluate the general well-being of cancer patients. FACT-G score ranges from 0 (never) to 4 (absolutely), with a higher score indicating a better quality of life.25,26
Results
Among the 5 patients, 1 patient discontinued the SVBP treatment because of pain on injection during the procedure, and the other 4 patients successfully completed the treatment course. Of the 4 patients who completed the treatment, the average VAS score was reduced from 8.75 to 2.75. The average WHO CIPN grade was decreased from 2.5 to 1. The average FACT-G score was increased from 68 to 75.75; however, on closer inspection, only the physical section score was raised from 10.5 to 18.5 with no notable differences shown in scores of other sections (Table 1). One patient taking analgesics (gabapentin 100 mg, acetaminophen 325 mg, and tramadol HCl 37.5 mg tid) could completely cease all medications. There were no related adverse side effects such as allergic reactions.
Discussion
CIPN is a common but serious clinical problem induced by exposure to several frequently used chemotherapeutic agents. 1 Although the pathophysiological mechanisms of CIPN have not been fully elucidated, CIPN is often associated with axonal degeneration. Axonopathy can occur weeks to months after initial exposure to medication and may continue after withdrawal of the drug. In some cases, it is irreversible. 27 Symptoms of CIPN include pain, paresthesia, hyperesthesia, impaired vibration and joint positional senses, ataxia, myalgia, and muscle weakness. Hypersensitivity to touch and other sensations develops. Such symptoms may cause difficulties with daily activities and greatly compromise the patients’ quality of life.4,28 In spite of many efforts to treat CIPN, currently there is no standard treatment protocol for the prevention, mitigation, or management of CIPN. These limitations of pharmacological options brought on the need for alternative treatment options that are effective and well tolerated, without interfering with anticancer treatments.
This study suggests that melittin, when administered according to an acupuncture study protocol to patients with screened BV allergy, is safe enough to be considered for future investigation. Allergic reactions such as local swelling, itching, pain, and, in some severe cases, anaphylactic shock have been the major concern for practitioners and patients using standard bee venom. 29 By removing allergenic antigens, such as phospholipase A2, hyaluronidase, and histamine, and by extracting the main component of the venom, melittin 14 decreases the probability of local allergic reactions as well as anaphylactic shock incidents.15,16 Four of 5 patients successfully completed the treatment with no evidence of any adverse events. One patient discontinued treatment because of pain during injection. We do not consider this event as indicating a safety issue with melittin but rather with injections. We recommend that future studies with a safety component screen people for injection sensitivity to more definitively assess the safety of pharmacopuncture.
There was a significant improvement in the short-term relieving of pain as measured by the VAS, which is a patient-reported outcome. In this small sample, there was only a nonsignificant trend toward improvement in the WHO CIPN scale, a physician-based assessment. In this report, only 3 treatments of SBVP over 1 week resulted in pain relief. SBVP was more rapid in managing CIPN symptoms when compared with reports on acupuncture for CIPN, which usually required 12 treatments over 6 weeks. We consider it very unlikely that all 4 patients would spontaneously improve in only 1 week without any intervention. It may take longer for objective improvements to manifest.
We speculate that pharmacopuncture relieves CIPN through an initial agonist activity followed by an irreversible antagonism of the glutamate transporter. In a rat neuropathic pain model, intrathecal pretreatment with naloxone (an opioid receptor antagonist) did not reverse the antihyperalgesic effect of BV, whereas pretreatment with idazoxan (an α2-adrenoceptor antagonist) completely blocked its effect. BV reduces the hyperalgesia associated with inflammation and is dependent on the activation of α2-adrenoceptors, but not opioid receptors. This may explain BV’s efficacy for patients with painful peripheral neuropathy, especially for those who are poorly responsive to opioid analgesics. 30 Intradermal injection of melittin produces temporary pain and a short-lived neurogenic-inflammation-skin temperature increase. 31 NMDA/non-NMDA receptors on nociceptors are involved in the melittin-induced neurogenic inflammation. Clinically, after 1 week, the pain appears to subside, suggesting that the glutamine-transporter mechanism is reset and hypersensitivity is reduced. More research will be needed to evaluate the different mechanisms of melittin in CIPN. Currently, we are analyzing whether this preparation of melittin interacts with the transporter X glutamine channel and its possible pharmacological mechanisms.
As the study was designed to be exploratory to establish preliminary data of safety, it holds many limitations as a case series. The biggest limitation of the study was the small sample size along with insufficient follow-up time and no control arm. For measurement tools, Total Neuropathy Score may be a better tool for prospective usage, since it blends both subjective and objective evaluations. It is a composite score (0-32 points) combining subjective sensory symptoms, subjective report of symptoms and amount of difficulty with daily activities, deep tendon reflexes, manual muscle testing for the wrist and ankle, pin sensibility, quantitative vibration thresholds, including nerve conduction studies of sural and peroneal nerves. 32 The time scale of response to determine whether there is more rapid recovery of neural function followed by pain relief should also be investigated in the future. However, our purpose for this study was to evaluate the short-term relief of pain.
In conclusion, the safety results of the SBVP therapy merits further investigation in a larger size trial for it to develop into a potential treatment for CIPN.
Footnotes
Jae-Woo Park and Ju-Hyun Jeon contributed equally. Other authors contributed to language translation, editing, and scientific advice.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The authors received no financial support for the research, authorship, and/or publication of this article.