ORIGINAL RESEARCH ARTICLE For reprint orders, please contact: [email protected]
N‑palmitoylethanolamide in the treatment of neuropathic pain associated with lumbosciatica
Practice Points
C Morera Domínguez*, A Díaz Martín1, F Garibo Ferrer2, MA Ibáñez Puertas3, A Leal Muro4, JC Martí González5, J Pombo Prieto6 & I Rosselló Taberna7 Although N‑palmitoylethanolamide has been demonstrated to have promising pharmacodynamic
effects for neuropathic pain management, clinical studies are lacking. Only patients with pain of neuropathic origin were included in the study. The decrease in pain according to the visual analog scale was greater in the N‑palmitoylethanolamide
group compared with the control group. The decrease in the visual analog scale was smaller than that observed in a double-blind study of
lumbosciatica patients not selected for neuropathic pain. For the results of bodily pain and physical component on the SF‑12® Health Survey, there was a
significant treatment effect. For the results of the mental component on the SF‑12 Health Survey, no significant treatment effect was
observed. Likewise, no significant treatment effect was observed on the Oswestry Disability Questionnaire. Further studies would be needed to confirm the usefulness of this agent in the treatment of neuropathic
pain associated with lumbosciatica.
SUMMARY
Aims: To investigate the effectiveness of N‑palmitoylethanolamide (PEA) in the treatment of neuropathic pain due to lumbosciatica. Materials & methods: Patients with neuropathic pain were assigned to standard treatment plus PEA (600 mg/day) or stan‑ dard treatment for 30 days. Changes in visual analog scale, and score on Oswestry Disability Index and SF‑12® Health Survey were assessed at baseline and follow-up. Results: The mean age of the 118 patients evaluated was 48.4 years, and 47 (40.9%) were women. In the group comparison, significantly larger improvements were seen in the PEA group for visual analog Clínica Rincón, Málaga, Spain Clínica Quirón, Valencia, Spain 3 Clínica MAZ, Zaragoza, Spain 4 Mutua Universal MUGENAT, Cáceres, Spain 5 Hospital San Rafael, Madrid, Spain 6 Complejo Hospitalario Universitario A Coruña CHUAC, A Coruña, Spain 7 Data Support, Barcelona, Spain *Author for correspondence: Hospital Universitario Mútua de Terrassa, Plaça Doctor Robert, Terrassa, Spain; Tel.: +34 93 93 736 50 50; [email protected] 1 2
10.2217/PMT.12.5 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(2), 119–124
part of
ISSN 1758-1869
119
Original research article Morera Domínguez, Díaz Martín, Garibo Ferrer et al. scale and the physical component of the SF‑12 Health Survey. Conclusion: The addition of PEA to standard treatment shows an improvement in pain relief in patients with neuropathic pain due to lumbosciatica. PEA was well tolerated. Future investigations of the role of PEA in the treatment of neuropathic pain might help to define novel therapeutic strategies for the treatment of this kind of neuropathic pain. Estimates in the prevalence of lumbosciatica vary greatly, from 1.2 to 43%, depending on the population studied and the definitions used [1] . For many patients, the prognosis is good, as indicated by a placebo-controlled trial of 208 patients in which 60% of the patients treated with placebo had recovered within 3 months and 70% within 12 months [2] . This implies, however, that there is still a sizeable proportion of patients who will still be experiencing symptoms after 1 year. Bed rest was recommended for a long time, but a systematic review of the evidence showed that bed-rest was less effective than remaining active for patients with acute lower back pain, and no differences were found in the case of lumbosciatica [3] . Other conservative treatments include analgesics or NSAIDs and epidural steroid injections, as well as treatments such as spinal manipulation, acupuncture, traction therapy, physical therapy and behavioral treatment [4] . In several cases, surgery may be considered and, although the initial outcomes may be beneficial, it is not clear whether the results are any better than conservative treatment in the long term [5] . Given the often severe impact on quality of life [6] , there is a need for new treatments for neuropathic pain caused by conditions such as lumbosciatica. One potentially promising agent is N‑palmitoylethanolamide (PEA), a naturally occurring and endogenous lipid that was identified several decades ago [7] . Recently, interest in this agent has been revived thanks to the finding that it can act as a cannabinoid mimetic, given that one of its structural analogs, anandamide, is an endogenous ligand for cannabinoid receptors [8] . Despite the apparent potential of PEA as a useful agent for the management of pain, little clinical experience is available. A placebo-controlled trial of 636 patients with lumbosciatica investigated the effect of two doses of PEA (300 mg and 600 mg) administered for 21 days [9] . Both dose levels were found to be significantly more effective than placebo at reducing pain (measured using a visual analog scale [VAS]) and the 600 mg dose group was also found to be
120
Pain Manage. (2012) 2(2)
more effective than the 300 mg dose group. The aim of the present study is to investigate the effectiveness of a commercial preparation of PEA (Normast®, Epitech group, Milan, Italy) in relieving neuropathic pain due to lumbosciatica. Patients & methods This was a prospective study performed in seven Spanish medical centers in the usual clinical practice. The study comprised a screening/ baseline visit and a follow-up visit at day 30. At the screening visit, consecutive patients were checked for eligibility. To be included, patients had to be between 18 and 65 years and had to experience chronic neuropathic pain resulting from lumbosciatica for at least 6 weeks. In addition, they had to have a score of ≥4 on a VAS for pain of 0–10, and also four or more affirmative responses to the neuropathic pain diagnostic questionnaire DN4 – a questionnaire designed to aid the diagnosis of neuropathic pain [10] . This questionnaire is formed of four questions with ten possible responses; a higher score indicates greater certainty of neuropathic pain. Patients were excluded if they were pregnant, had a food allergy, were receiving concomitant treatment that might affect the peripheral nervous system, had a concurrent illness that might give rise to similar symptoms or had participated in a clinical trial in the preceding 4 weeks. Those that agreed to participate were asked for informed consent and numbers were assigned to them according to the order of recruitment. Patients with an odd number were assigned to standard treatment (NSAIDS, analgesics, muscle relaxants, corticosteroids – although the exact nature of this treatment could vary by center, investigator and characteristics of the patient) plus PEA. The remaining patients received only standard treatment for pain management. At the screening/baseline visit, the study questionnaires SF‑12® and Oswestry Disability Index (ODI) were administered and data of other study variables including tolerability were collected (see below). After 30 days, the patients attended a follow-up visit and data on the efficacy and safety outcomes were collected.
future science group
N‑palmitoylethanolamide in the treatment of neuropathic pain Treatment
In addition to the habitual treatment prescribed by the investigator at the initial study visit, those patients assigned to the active treatment group took 600 mg of PEA per day (one 300 mg tablet in the morning and one in the afternoon). Compliance was assessed at the follow-up study visit by asking patients for the number of unused tablets. Study variables
Changes in the pain of patients over the study period (i.e., between the baseline visit and the follow-up visit) were assessed using a VAS for pain (scale ranging from 0–10 with higher scores indicating greater pain), a validated version of the short-form SF‑12 Health Survey and the Oswestry Disability Questionnaire. The SF‑12, a shortened version of the SF‑36® that selects the 12 most representative items, has been translated into Spanish and validated [11] . This questionnaire provides an overview of the patient’s quality of life. Scores can range from 1 to 100; the nearer a score to 100, the better the patient’s quality of life. The Oswestry Disability Questionnaire is used to calculate the ODI, one of the main condition-specific outcome measures used in the management of spinal disorders [12] . The questionnaire consists of ten questions about different aspects of spinal injury (with five possible answers to each question). The scores on each question are added together and multiplied by two to give a result in percentage disability (higher scores indicating greater disability). Treatment outcomes were further assessed by analyzing changes in VAS at follow-up and a physician and patient assessment of treatment (on a scale of 1–5). Tolerability was assessed by recording adverse events (AEs). A telephone number was supplied for reporting AEs between visits and patients were questioned for possible AEs at the follow-up visit.
Original research article
Table 1. Demographic characteristics of the groups treated and not treated (control group) with N‑palmitoylethanolamide.
Sex
Female Male
Age Weight Height Currently working
N‑palmitoylethanolamide (n = 64)
Control (n = 54)
27 (42.2%) 36 (56.3%) 49.5 ± 9.86 76.1 ± 12.14 169.3 ± 8.93 28 (43.8%)
20 (37.0%) 29 (53.7%) 47.6 ± 12.08 73.9 ± 13.36 168.4 ± 8.12 22 (40.7%)
Statistical analysis
Once the data had been checked for possible errors and had been entered into a database, descriptive statistics were calculated (mean, standard deviation) for baseline and follow-up data. For variables with a normal distribution, according to the Kolmogorov–Smirnov test, 95% CIs were calculated and differences with respect to baseline assessed using a Student’s t-test. An analysis of variance (or the Welch and Brown– Forsythe test in the event of lack of homogeneity in the data) was used to assess differences between groups from baseline. For qualitative variables, the c2 test was used. Significance was set at p
N‑palmitoylethanolamide in the treatment of neuropathic pain associated with lumbosciatica
Practice Points
C Morera Domínguez*, A Díaz Martín1, F Garibo Ferrer2, MA Ibáñez Puertas3, A Leal Muro4, JC Martí González5, J Pombo Prieto6 & I Rosselló Taberna7 Although N‑palmitoylethanolamide has been demonstrated to have promising pharmacodynamic
effects for neuropathic pain management, clinical studies are lacking. Only patients with pain of neuropathic origin were included in the study. The decrease in pain according to the visual analog scale was greater in the N‑palmitoylethanolamide
group compared with the control group. The decrease in the visual analog scale was smaller than that observed in a double-blind study of
lumbosciatica patients not selected for neuropathic pain. For the results of bodily pain and physical component on the SF‑12® Health Survey, there was a
significant treatment effect. For the results of the mental component on the SF‑12 Health Survey, no significant treatment effect was
observed. Likewise, no significant treatment effect was observed on the Oswestry Disability Questionnaire. Further studies would be needed to confirm the usefulness of this agent in the treatment of neuropathic
pain associated with lumbosciatica.
SUMMARY
Aims: To investigate the effectiveness of N‑palmitoylethanolamide (PEA) in the treatment of neuropathic pain due to lumbosciatica. Materials & methods: Patients with neuropathic pain were assigned to standard treatment plus PEA (600 mg/day) or stan‑ dard treatment for 30 days. Changes in visual analog scale, and score on Oswestry Disability Index and SF‑12® Health Survey were assessed at baseline and follow-up. Results: The mean age of the 118 patients evaluated was 48.4 years, and 47 (40.9%) were women. In the group comparison, significantly larger improvements were seen in the PEA group for visual analog Clínica Rincón, Málaga, Spain Clínica Quirón, Valencia, Spain 3 Clínica MAZ, Zaragoza, Spain 4 Mutua Universal MUGENAT, Cáceres, Spain 5 Hospital San Rafael, Madrid, Spain 6 Complejo Hospitalario Universitario A Coruña CHUAC, A Coruña, Spain 7 Data Support, Barcelona, Spain *Author for correspondence: Hospital Universitario Mútua de Terrassa, Plaça Doctor Robert, Terrassa, Spain; Tel.: +34 93 93 736 50 50; [email protected] 1 2
10.2217/PMT.12.5 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(2), 119–124
part of
ISSN 1758-1869
119
Original research article Morera Domínguez, Díaz Martín, Garibo Ferrer et al. scale and the physical component of the SF‑12 Health Survey. Conclusion: The addition of PEA to standard treatment shows an improvement in pain relief in patients with neuropathic pain due to lumbosciatica. PEA was well tolerated. Future investigations of the role of PEA in the treatment of neuropathic pain might help to define novel therapeutic strategies for the treatment of this kind of neuropathic pain. Estimates in the prevalence of lumbosciatica vary greatly, from 1.2 to 43%, depending on the population studied and the definitions used [1] . For many patients, the prognosis is good, as indicated by a placebo-controlled trial of 208 patients in which 60% of the patients treated with placebo had recovered within 3 months and 70% within 12 months [2] . This implies, however, that there is still a sizeable proportion of patients who will still be experiencing symptoms after 1 year. Bed rest was recommended for a long time, but a systematic review of the evidence showed that bed-rest was less effective than remaining active for patients with acute lower back pain, and no differences were found in the case of lumbosciatica [3] . Other conservative treatments include analgesics or NSAIDs and epidural steroid injections, as well as treatments such as spinal manipulation, acupuncture, traction therapy, physical therapy and behavioral treatment [4] . In several cases, surgery may be considered and, although the initial outcomes may be beneficial, it is not clear whether the results are any better than conservative treatment in the long term [5] . Given the often severe impact on quality of life [6] , there is a need for new treatments for neuropathic pain caused by conditions such as lumbosciatica. One potentially promising agent is N‑palmitoylethanolamide (PEA), a naturally occurring and endogenous lipid that was identified several decades ago [7] . Recently, interest in this agent has been revived thanks to the finding that it can act as a cannabinoid mimetic, given that one of its structural analogs, anandamide, is an endogenous ligand for cannabinoid receptors [8] . Despite the apparent potential of PEA as a useful agent for the management of pain, little clinical experience is available. A placebo-controlled trial of 636 patients with lumbosciatica investigated the effect of two doses of PEA (300 mg and 600 mg) administered for 21 days [9] . Both dose levels were found to be significantly more effective than placebo at reducing pain (measured using a visual analog scale [VAS]) and the 600 mg dose group was also found to be
120
Pain Manage. (2012) 2(2)
more effective than the 300 mg dose group. The aim of the present study is to investigate the effectiveness of a commercial preparation of PEA (Normast®, Epitech group, Milan, Italy) in relieving neuropathic pain due to lumbosciatica. Patients & methods This was a prospective study performed in seven Spanish medical centers in the usual clinical practice. The study comprised a screening/ baseline visit and a follow-up visit at day 30. At the screening visit, consecutive patients were checked for eligibility. To be included, patients had to be between 18 and 65 years and had to experience chronic neuropathic pain resulting from lumbosciatica for at least 6 weeks. In addition, they had to have a score of ≥4 on a VAS for pain of 0–10, and also four or more affirmative responses to the neuropathic pain diagnostic questionnaire DN4 – a questionnaire designed to aid the diagnosis of neuropathic pain [10] . This questionnaire is formed of four questions with ten possible responses; a higher score indicates greater certainty of neuropathic pain. Patients were excluded if they were pregnant, had a food allergy, were receiving concomitant treatment that might affect the peripheral nervous system, had a concurrent illness that might give rise to similar symptoms or had participated in a clinical trial in the preceding 4 weeks. Those that agreed to participate were asked for informed consent and numbers were assigned to them according to the order of recruitment. Patients with an odd number were assigned to standard treatment (NSAIDS, analgesics, muscle relaxants, corticosteroids – although the exact nature of this treatment could vary by center, investigator and characteristics of the patient) plus PEA. The remaining patients received only standard treatment for pain management. At the screening/baseline visit, the study questionnaires SF‑12® and Oswestry Disability Index (ODI) were administered and data of other study variables including tolerability were collected (see below). After 30 days, the patients attended a follow-up visit and data on the efficacy and safety outcomes were collected.
future science group
N‑palmitoylethanolamide in the treatment of neuropathic pain Treatment
In addition to the habitual treatment prescribed by the investigator at the initial study visit, those patients assigned to the active treatment group took 600 mg of PEA per day (one 300 mg tablet in the morning and one in the afternoon). Compliance was assessed at the follow-up study visit by asking patients for the number of unused tablets. Study variables
Changes in the pain of patients over the study period (i.e., between the baseline visit and the follow-up visit) were assessed using a VAS for pain (scale ranging from 0–10 with higher scores indicating greater pain), a validated version of the short-form SF‑12 Health Survey and the Oswestry Disability Questionnaire. The SF‑12, a shortened version of the SF‑36® that selects the 12 most representative items, has been translated into Spanish and validated [11] . This questionnaire provides an overview of the patient’s quality of life. Scores can range from 1 to 100; the nearer a score to 100, the better the patient’s quality of life. The Oswestry Disability Questionnaire is used to calculate the ODI, one of the main condition-specific outcome measures used in the management of spinal disorders [12] . The questionnaire consists of ten questions about different aspects of spinal injury (with five possible answers to each question). The scores on each question are added together and multiplied by two to give a result in percentage disability (higher scores indicating greater disability). Treatment outcomes were further assessed by analyzing changes in VAS at follow-up and a physician and patient assessment of treatment (on a scale of 1–5). Tolerability was assessed by recording adverse events (AEs). A telephone number was supplied for reporting AEs between visits and patients were questioned for possible AEs at the follow-up visit.
Original research article
Table 1. Demographic characteristics of the groups treated and not treated (control group) with N‑palmitoylethanolamide.
Sex
Female Male
Age Weight Height Currently working
N‑palmitoylethanolamide (n = 64)
Control (n = 54)
27 (42.2%) 36 (56.3%) 49.5 ± 9.86 76.1 ± 12.14 169.3 ± 8.93 28 (43.8%)
20 (37.0%) 29 (53.7%) 47.6 ± 12.08 73.9 ± 13.36 168.4 ± 8.12 22 (40.7%)
Statistical analysis
Once the data had been checked for possible errors and had been entered into a database, descriptive statistics were calculated (mean, standard deviation) for baseline and follow-up data. For variables with a normal distribution, according to the Kolmogorov–Smirnov test, 95% CIs were calculated and differences with respect to baseline assessed using a Student’s t-test. An analysis of variance (or the Welch and Brown– Forsythe test in the event of lack of homogeneity in the data) was used to assess differences between groups from baseline. For qualitative variables, the c2 test was used. Significance was set at p
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