- Email: [email protected]
Use of topical medication in orofacial neuropathic pain: a retrospective study
Use of topical medication in orofacial neuropathic pain: a retrospective study Gary Heir, DMD,a Scott Karolchek, MS, RPH, DNM,b Mythili Kalladka, BDS, BDS,c Archana Vishwanath, BDS,d Julyana Gomes, DDS,e Raashi Khatri, BDS,f Cibele Nasri, DDS,g Eli Eliav, DMD, PhD,h and Sowmya Ananthan, BDSi Newark, NJ UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY AND PHARMACY CREATIONS
Objective. The objective of this study was to evaluate the effect of topical medications as a single treatment or in combination with systemic medications in the treatment of orofacial neuropathic pain conditions. Study design. A retrospective chart review of 39 patients treated for orofacial neuropathic pain at the Orofacial Pain Clinic in the New Jersey Dental School was performed. In line with the treatment selection, the subjects were divided into 3 groups: topical medications only (n ⫽ 12), systemic medications only (n ⫽ 10), and a combination of both (n ⫽ 17). Results. The starting pain level as expressed in pain Visual Analog Scale for the 3 groups was significantly different. The combined treatment group baseline pain level (7.5 ⫾ 0.403 SEM; P ⫽ .0015) and the systemic treatment only group pain level (8.6 ⫾ 0.611 SEM; P ⫽ .0375) was significantly elevated compared to the topical only group (6.1 ⫾ 0.716 SEM; P ⫽ .1057). Following treatment, pain level was significantly reduced in all 3 groups. The combined group had the highest pain relief (52.0 ⫾ 6.676 SEM % reduction; P ⬍ .0001) followed by the systemic-only group (40.6 ⫾ 9.727 SEM % reduction; P ⫽ .0029) and the topicals-only group (40.9 ⫾ 10.775 SEM% reduction; P ⫽ .0048). The time taken for the topical treatment only to act was significantly shorter (3 weeks ⫾ 0.479 SEM; P ⫽ .0015) when compared with the systemic-only (4 weeks ⫾ 0.772 SEM; P ⫽ .3629) and the combined group (5.5 weeks ⫾ 0.912 SEM; P ⫽ .1738). Conclusion. Topical medication as single treatment or in combination with systemic medications can reduce orofacial neuropathic pain severity. Further prospective research should be performed to validate this treatment option. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:466-9)
Neuropathic pain is defined as a condition that is initiated or caused by a primary lesion or dysfunction in the nervous system.1 Etiologies of neuropathic pain vary a
Clinical Professor, Clinical Director, Department of Diagnostic Sciences, Division of Orofacial Pain, University of Medicine and Dentistry of New Jersey. b Co-director, Pharmacy Creations. c Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. d Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. e Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. f Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. g Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. h Program Director, Orofacial Pain Program, Department of Diagnostic Sciences, Division of Orofacial Pain, University of Medicine and Dentistry of New Jersey. i Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. Received for publication Jun 19, 2007; returned for revision Sep 26, 2007; accepted for publication Sep 26, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.09.030
466
from local trauma to central nervous system pathologies. Traumatic neuropathies can occur following dental procedures such as extractions, endodontic treatment, and dental implant insertion.2-5 The treatment for neuropathic pain in most cases is pharmacological with medications that include antidepressants, analgesics, and antiepileptics. The efficacy of these medications varies from patient to patient depending on a variety of factors such as the pain location, age of patient, and/or any comorbid systemic diseases.6,7 Pharmacologic treatment is often accompanied by unpleasant side effects such as sedation and dizziness. Moreover, interaction with other medications may contradict the use of these medications or prevent their use in the medically compromised or elderly patient.8 An alternate medication delivery method, in use clinically for several years, is topical medication. This method has been reported by several authors to be clinically useful for neuropathic pain, but has not yet studied in the orofacial region.9-12 Topical medications are used to treat only a specific peripheral target with minimal or no systemic effect.11-13 This is in contrast to transdermal compounds, which are designed to transport medications through the skin or mucosa as an alternative to oral or parenteral administration.14
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This article will describe retrospective comparison of the results of different methods of treatment from 39 patients with neuropathic orofacial pain who were treated with either systemic or topical medications or a combination of both. METHODS A retrospective chart review was conducted at the University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Dental School, Orofacial Pain Clinic, where patients with neuropathic pain conditions are seen on a regular basis. The Institutional Review Board of the UMDNJ Newark campus approved the study. Charts of 39 patients who were diagnosed with a neuropathic pain condition such as deafferentation pain, traumatic neuroma, or trigeminal or glossopharyngeal neuralgia were included in the study. The diagnosis was done based on the International Association for the Study of Pain guidelines15 and the history provided by the patient. Patients who had a diagnosis of neuropathic pain along with other conditions were excluded from the study. The patients varied in age from 18 to 65 years. There were 32 female and 7 males patients. The patients were treated over a period of 8 years (from 1999 to 2006). The patients were subdivided into 3 categories according to the treatment protocol. The categories were (1) topical treatment only (n⫽12), (2) systemic treatment only (n⫽10), and (3) a combined topical and systemic treatment group (n⫽17). The “topicals only” group had 3 patients with deafferentation pain, 4 with trigeminal neuralgia, 4 with traumatic neuroma, and 1 with deafferentation pain and neuroma (total⫽ 12). The “systemic only” group had 3 patients with deafferentation pain, 4 with trigeminal neuralgia, 2 with glossopharyngeal neuralgia, and 1 with deafferentation pain and traumatic neuroma (total ⫽ 10). In the “combined treatment” group there were 12 patients with deafferentation pain, 3 patients with trigeminal neuralgia and 2 patients with deafferentation pain and traumatic neuroma (total ⫽ 17). The systemic medications prescribed were medications commonly used to treat neuropathic pain conditions: antiepileptics such as carbamazepine, oxcarbazepine, gabapentin, and pregabalin for neuralgic pain or tricyclic antidepressants such as amitryptyline and nortryptyline for deafferentation pain. The dosage prescribed and subsequent changes in dosage during follow-up visits were collected from the records. The dosages were prescribed based on the severity of the patient’s pain, so were not similar for all patients. All patients were treated by the same attending clinician (G.H.). The topical medication was formulated by the same
Heir et al. 467
compounding pharmacy for all patients, containing carbamazepine 4%, lidocaine 1%, ketoprofen 4%, ketamine 4%, and gabapentin 4% in a Pluronic lecithin organogel and anhydrous gel base (nonactive vehicle). The patients were asked to apply topical medication to the affected area 4 to 6 times per day. Pain levels were recorded routinely in the Orofacial Pain Clinic using a visual analogue scale (VAS) at every visit. For each patient the level of pain prior to start of treatment and at follow-up visits was recorded in the chart. The follow-up visits were scheduled usually 2 weeks after the initial visit. The time for onset of action of the medication also was recorded. The medication was considered effective if the patient reported at least 30% pain relief and was recorded on the VAS. If the patient did not report any pain relief, they were asked to continue applying the topical medication and if they were on systemic medication, the dosage was increased. The time taken for pain relief was calculated based on the patient reporting at least a 30% reduction in their pain level.16,17 Percentage pain relief was calculated as the difference between the initial VAS and posttreatment VAS divided by the initial VAS. Comparison was made for VAS scored before and after the treatment, pain relief, and time taken for pain relief as reported by the patients. Data were tabulated and analyzed using Statview 5 software (SAS Institute, Randolph, NJ). The alpha level for significance was set at 0.05. The 3 groups were compared by a factorial analysis of variance (ANOVA) followed by a pairwise comparison with Fisher’s protected least significant difference. For within the groups, data for before and after treatment comparison, repeated measures ANOVA (RANOVA) was employed. RESULTS The initial pain level for the 3 groups was different (ANOVA: F ⫽ 6.038, P ⫽ .0055). The combined treatment group baseline pain level was 7.5 ⫾ 0.403 SEM (standard error of the mean) (P ⫽ .0015) and the systemic only group pain level was 8.6 ⫾ 0.611 SEM (P ⫽ .0375) on the VAS scale. Both were significantly elevated compared with the topical treatment group 6.1 ⫾ 0.716 SEM (P ⫽ .1057) (Fig. 1). Following treatment (i.e., at least 30% pain relief) (ANOVA for “pain after”: F ⫽ 1.204, P ⫽ .3117), pain level was significantly reduced in all 3 groups, although it was different for all 3 groups. The combined treatment group had the most relief of 52.0 ⫾ 6.676 SEM % pain reduction (from 7.5 to 3.6 on the VAS) (P ⬍ .0001). The systemic treatment group demonstrated 40.6 ⫾ 9.727 SEM % pain reduction (from 8.6 to 5.1 on the VAS) (P ⫽ .0029) and the topical treatment group demonstrated 40.9⫾ 10.775 SEM % pain reduction
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Heir et al.
10 9 8 7 6 5 4 3 2 1 0
*
70 60
*
Combined Systemic Topicals
Percentage
VAS
468
50 Combined Systemic Topicals
40 30 20 10 0
Fig. 2. Percentage pain relief obtained. Pain Before Treatment
Pain Following Treatment
Pain levels before and following treatment.
Fig. 1. Pain levels before and following treatment.
Combined Systemic Topicals
7
(from 6.1 to 3.6 on the VAS) (P ⫽ .0048). ANOVA for “percentage relief”: F ⫽ 0.570, P ⫽ .5704 (Fig. 2). The time taken (ANOVA: F ⫽ 3.254, P ⫽ .0502) for the topical treatment to reduce pain was significantly shorter (3.000 ⫾ 0.479 weeks SEM; P ⫽ .0015) when compared with the systemic only group (4.000 ⫾ 0.772 weeks SEM; P ⫽ .3629) and the combined group (5.500 ⫾ 0.912 weeks SEM; P ⫽ .1738) (Fig. 3). DISCUSSION The most important finding of this study is that topical treatment may be effective in the treatment of neuropathic orofacial pain, since a 30% reduction in pain levels is considered a good response.16,17 Topical medications seem to have increased effectiveness when the starting pain levels were mild to moderate. In cases of severe pain, there was a reduced effect. We postulate that this may be because of limited patient compliance with the use of topical medications alone in such cases. Combination strategies may be effective in reducing the risk of adverse drug reaction, drug tolerance, or addiction.18-20 Currently drugs used to manage neuropathic pain improve mood and quality of life. They are limited by side effects. The potential for combination pharmacotherapy is being explored.19,20 However, as a retrospective evaluation, the data collection had certain limitations. The pain relief felt by the patients was based on their subjective feeling and was not standardized. The time point at which the data were collected was not the same for all the patients. Furthermore, there may have been variability in the number of times the topical medication was applied during the day, which could affect the pain relief obtained. The topical group had less pain initially, which could account for better pain relief obtained. The dosage of the systemic medication was not the same for all patients as it was adjusted based on the severity of the patient’s pain. Although the treatment offered was based on the sever-
Weeks
6 5
*
4 3 2 1 0 Time taken for pain relief.
Fig. 3. Time taken for pain relief.
ity of pain felt by the patient, it was not standardized, as each group had different diagnoses and it would have complicated the results to analyze each group separately. Since the number of patients in each group was small, this could have reduced the power of the study. Despite possible shortcomings, this study does seem to indicate that topical delivery of medications to a painful treatment target represents a unique means by which to accomplish a local pharmacotherapeutic action.18,21 The topical medication can be ordered from a compounding pharmacy where it can be formulated to contain carbamazepine 4%, lidocaine 1%, ketoprofen 4%, ketamine 4%, and gabapentin 4%. Carbamazepine and gabapentin, which are anticonvulsant drugs, act by suppressing paroxysmal discharges and reducing neuronal hyperexcitability.22 Lidocaine, which is a local anesthetic, acts by blocking sodium channels, preventing nerve depolarization.23 Ketoprofen has anti-inflammatory activity.24 Last, ketamine blocks N-methyl-D-aspartate (NMDA) receptors, whose hyperactivity contributes to maintenance of neuropathic pain.25 The topical should have penetration enhancers such as anhydrous gels and bio-adhesive copolymers. These are used to carry the medication transdermally and transmucosally.26,27 The anhydrous gel base is composed of propylene glycol (PG), glycerin, and ethoxy diglycol (EG) in varying percentages depending on depth of penetration desired.
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Anhydrous gels via micelle and solubilization of oils and water activate chemicals that can penetrate the epidermis, which is lipid in nature. The solubilizing power of EG was found to be valuable for increasing the concentration gradient in the skin. It is also possible to modulate the depth of drug delivery.28-30 Increasing the concentration of EG limits the penetration depth of the gel. This “shallow” penetration is advantageous in targeting more superficial nerve endings in the dermal layer. In the clinical setting, this would be useful if a patient has a traumatic neuroma, area of deafferentation, or an intraoral trigger zone in cases of trigeminal neuralgia. A neurosensory stent can be fabricated to prevent the medication from being washed away by saliva. The patient can be asked to apply the topical medication in the affected area several times a day. This can potentially help patients who are intolerant of systemic medications, older patients,8 and medically compromised patients. Pain signaling involves complex mechanisms. For neuropathic pain, peripheral activity of afferent nerves is an important contributor to pain. These conditions can benefit from a localized application of topical medications31; combinations of agents targeting different pain mechanisms may be particularly useful. It is postulated31 that topical medications may play a role in desensitizing trigger zones and can reduce the peripheral sensibility of areas affected by deafferentation and neuroma formation. CONCLUSION Topical medications can provide rapid pain relief either alone or in combination with systemic medication. The effectiveness, indication, dosage, and components are still open to discussion. This pilot study can serve as the basis for further prospective studies on the subject. REFERENCES 1. Merskey H, Bogduk N, International Association for the Study of Pain. IPT, Classification of Chronic Pain, 2nd ed. IASP Task Force on Taxonomy. Seattle (WA): IASP Press; 1994. pp. 209-14. 2. Truelove E. Management issues of neuropathic trigeminal pain from a dental perspective. J Orofac Pain 2004;18(4):374-80. 3. Vickers ER, Cousins MJ. Neuropathic orofacial pain, part 1—prevalence and pathophysiology. Aust Endod J 2000;26(1):19-26. 4. Delcanho RE. Neuropathic implications of prosthodontic treatment. J Prosthet Dent 1995;73(2):146-52. 5. Gregg JM. Neuropathic complications of mandibular implant surgery: review and case presentations. Ann R Australas Coll Dent Surg 2000;15:176-80. 6. Lewis MA, Sankar V, De Laat A, Benoliel R. Management of neuropathic orofacial pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(Suppl):S32 e1-24. 7. Watson CP. Management issues of neuropathic trigeminal pain from a medical perspective. J Orofac Pain 2004;18(4):366-73. 8. Feinberg SD. Prescribing analgesics. How to improve function and avoid toxicity when treating chronic pain. Geriatrics 2000;55(11):44-62. 9. Collins SD, Chessell IP. Emerging therapies for neuropathic pain. Expert Opin Emerg Drugs 2005;10(1):95-108.
Heir et al. 469 10. Colombo B, Annovazzi PO, Comi G. Medications for neuropathic pain: current trends. Neurol Sci 2006;27(Suppl 2):S183-9. 11. McCleane G. Topical analgesics. Med Clin North Am 2007;91(1):125-39. 12. Padilla M, Clark GT, Merrill RL. Topical medications for orofacial neuropathic pain: a review. J Am Dent Assoc 2000;131(2):184-95. 13. Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995;37(2):246-53. 14. Priano L, Gasco MR, Mauro A. Transdermal treatment options for neurological disorders: impact on the elderly. Drugs Aging 2006;23(5):357-75. 15. Giamberardino MA. Pain 2002: an updated review refresher course syllabus. 10th World Congress on Pain. Seattle (WA): IASP Press; 2002. 16. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94(2):149-58. 17. Lund JP LG, Dubner R, Sessle BJ. Orofacial pain: from basic science to clinical management. Chicago: Quintessence; 2001. 18. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical amitriptyline and ketamine in neuropathic pain syndromes: an openlabel study. J Pain 2005;6(10):644-9. 19. Gilron I, Max MB. Combination pharmacotherapy for neuropathic pain: current evidence and future directions. Expert Rev Neurother 2005;5(6):823-30. 20. Jackson KC 2nd. Pharmacotherapy for neuropathic pain. Pain Pract 2006;6(1):27-33. 21. Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 2003;19(5):323-8. 22. Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain 2002;6(Suppl A):61-8. 23. Covino BG. Pharmacology of local anesthetic agents. Ration Drug Ther 1987;21(8):1-9. 24. Kyuki K. [Evaluation of nonsteroidal anti-inflammatory drugs (NSAID) intended for use as topical anti-inflammatory drugs.] Nippon Yakurigaku Zasshi 1982;79(6):461-85. Japanese. 25. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 1994;56(1):51-7. 26. Posner R. Liposomes. J Drugs Dermatol 2002;1(2):161-4. 27. Mura P, Faucci MT, Bramanti G, Corti P. Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations. Eur J Pharm Sci 2000;9(4):365-72. 28. Remane Y, Leopold CS, Maibach HI. Percutaneous penetration of methyl nicotinate from ointments using the laser Doppler technique: bioequivalence and enhancer effects. J Pharmacokinet Pharmacodyn 2006;33(6):719-35. 29. Shin SC, Cho CW. Enhanced transdermal delivery of pranoprofen from the bioadhesive gels. Arch Pharm Res 2006;29(10):928-33. 30. Silvander M, Ringstad L, Ghadially R, Skold T. A new water-based topical carrier with polar skin-lipids. Lipids Health Dis 2006;5:12. 31. Sawynok J. Topical and peripherally acting analgesics. Pharmacological reviews 2003;55(1):1-20. Reprint requests: Gary Heir, DMD Department of Diagnostic Sciences Division of Orofacial Pain 110 Bergen Street PO Box 1709 Newark, NJ 07101-1709 [email protected]
Objective. The objective of this study was to evaluate the effect of topical medications as a single treatment or in combination with systemic medications in the treatment of orofacial neuropathic pain conditions. Study design. A retrospective chart review of 39 patients treated for orofacial neuropathic pain at the Orofacial Pain Clinic in the New Jersey Dental School was performed. In line with the treatment selection, the subjects were divided into 3 groups: topical medications only (n ⫽ 12), systemic medications only (n ⫽ 10), and a combination of both (n ⫽ 17). Results. The starting pain level as expressed in pain Visual Analog Scale for the 3 groups was significantly different. The combined treatment group baseline pain level (7.5 ⫾ 0.403 SEM; P ⫽ .0015) and the systemic treatment only group pain level (8.6 ⫾ 0.611 SEM; P ⫽ .0375) was significantly elevated compared to the topical only group (6.1 ⫾ 0.716 SEM; P ⫽ .1057). Following treatment, pain level was significantly reduced in all 3 groups. The combined group had the highest pain relief (52.0 ⫾ 6.676 SEM % reduction; P ⬍ .0001) followed by the systemic-only group (40.6 ⫾ 9.727 SEM % reduction; P ⫽ .0029) and the topicals-only group (40.9 ⫾ 10.775 SEM% reduction; P ⫽ .0048). The time taken for the topical treatment only to act was significantly shorter (3 weeks ⫾ 0.479 SEM; P ⫽ .0015) when compared with the systemic-only (4 weeks ⫾ 0.772 SEM; P ⫽ .3629) and the combined group (5.5 weeks ⫾ 0.912 SEM; P ⫽ .1738). Conclusion. Topical medication as single treatment or in combination with systemic medications can reduce orofacial neuropathic pain severity. Further prospective research should be performed to validate this treatment option. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:466-9)
Neuropathic pain is defined as a condition that is initiated or caused by a primary lesion or dysfunction in the nervous system.1 Etiologies of neuropathic pain vary a
Clinical Professor, Clinical Director, Department of Diagnostic Sciences, Division of Orofacial Pain, University of Medicine and Dentistry of New Jersey. b Co-director, Pharmacy Creations. c Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. d Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. e Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. f Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. g Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. h Program Director, Orofacial Pain Program, Department of Diagnostic Sciences, Division of Orofacial Pain, University of Medicine and Dentistry of New Jersey. i Master’s candidate, Orofacial Pain Program, University of Medicine and Dentistry of New Jersey. Received for publication Jun 19, 2007; returned for revision Sep 26, 2007; accepted for publication Sep 26, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.09.030
466
from local trauma to central nervous system pathologies. Traumatic neuropathies can occur following dental procedures such as extractions, endodontic treatment, and dental implant insertion.2-5 The treatment for neuropathic pain in most cases is pharmacological with medications that include antidepressants, analgesics, and antiepileptics. The efficacy of these medications varies from patient to patient depending on a variety of factors such as the pain location, age of patient, and/or any comorbid systemic diseases.6,7 Pharmacologic treatment is often accompanied by unpleasant side effects such as sedation and dizziness. Moreover, interaction with other medications may contradict the use of these medications or prevent their use in the medically compromised or elderly patient.8 An alternate medication delivery method, in use clinically for several years, is topical medication. This method has been reported by several authors to be clinically useful for neuropathic pain, but has not yet studied in the orofacial region.9-12 Topical medications are used to treat only a specific peripheral target with minimal or no systemic effect.11-13 This is in contrast to transdermal compounds, which are designed to transport medications through the skin or mucosa as an alternative to oral or parenteral administration.14
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This article will describe retrospective comparison of the results of different methods of treatment from 39 patients with neuropathic orofacial pain who were treated with either systemic or topical medications or a combination of both. METHODS A retrospective chart review was conducted at the University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Dental School, Orofacial Pain Clinic, where patients with neuropathic pain conditions are seen on a regular basis. The Institutional Review Board of the UMDNJ Newark campus approved the study. Charts of 39 patients who were diagnosed with a neuropathic pain condition such as deafferentation pain, traumatic neuroma, or trigeminal or glossopharyngeal neuralgia were included in the study. The diagnosis was done based on the International Association for the Study of Pain guidelines15 and the history provided by the patient. Patients who had a diagnosis of neuropathic pain along with other conditions were excluded from the study. The patients varied in age from 18 to 65 years. There were 32 female and 7 males patients. The patients were treated over a period of 8 years (from 1999 to 2006). The patients were subdivided into 3 categories according to the treatment protocol. The categories were (1) topical treatment only (n⫽12), (2) systemic treatment only (n⫽10), and (3) a combined topical and systemic treatment group (n⫽17). The “topicals only” group had 3 patients with deafferentation pain, 4 with trigeminal neuralgia, 4 with traumatic neuroma, and 1 with deafferentation pain and neuroma (total⫽ 12). The “systemic only” group had 3 patients with deafferentation pain, 4 with trigeminal neuralgia, 2 with glossopharyngeal neuralgia, and 1 with deafferentation pain and traumatic neuroma (total ⫽ 10). In the “combined treatment” group there were 12 patients with deafferentation pain, 3 patients with trigeminal neuralgia and 2 patients with deafferentation pain and traumatic neuroma (total ⫽ 17). The systemic medications prescribed were medications commonly used to treat neuropathic pain conditions: antiepileptics such as carbamazepine, oxcarbazepine, gabapentin, and pregabalin for neuralgic pain or tricyclic antidepressants such as amitryptyline and nortryptyline for deafferentation pain. The dosage prescribed and subsequent changes in dosage during follow-up visits were collected from the records. The dosages were prescribed based on the severity of the patient’s pain, so were not similar for all patients. All patients were treated by the same attending clinician (G.H.). The topical medication was formulated by the same
Heir et al. 467
compounding pharmacy for all patients, containing carbamazepine 4%, lidocaine 1%, ketoprofen 4%, ketamine 4%, and gabapentin 4% in a Pluronic lecithin organogel and anhydrous gel base (nonactive vehicle). The patients were asked to apply topical medication to the affected area 4 to 6 times per day. Pain levels were recorded routinely in the Orofacial Pain Clinic using a visual analogue scale (VAS) at every visit. For each patient the level of pain prior to start of treatment and at follow-up visits was recorded in the chart. The follow-up visits were scheduled usually 2 weeks after the initial visit. The time for onset of action of the medication also was recorded. The medication was considered effective if the patient reported at least 30% pain relief and was recorded on the VAS. If the patient did not report any pain relief, they were asked to continue applying the topical medication and if they were on systemic medication, the dosage was increased. The time taken for pain relief was calculated based on the patient reporting at least a 30% reduction in their pain level.16,17 Percentage pain relief was calculated as the difference between the initial VAS and posttreatment VAS divided by the initial VAS. Comparison was made for VAS scored before and after the treatment, pain relief, and time taken for pain relief as reported by the patients. Data were tabulated and analyzed using Statview 5 software (SAS Institute, Randolph, NJ). The alpha level for significance was set at 0.05. The 3 groups were compared by a factorial analysis of variance (ANOVA) followed by a pairwise comparison with Fisher’s protected least significant difference. For within the groups, data for before and after treatment comparison, repeated measures ANOVA (RANOVA) was employed. RESULTS The initial pain level for the 3 groups was different (ANOVA: F ⫽ 6.038, P ⫽ .0055). The combined treatment group baseline pain level was 7.5 ⫾ 0.403 SEM (standard error of the mean) (P ⫽ .0015) and the systemic only group pain level was 8.6 ⫾ 0.611 SEM (P ⫽ .0375) on the VAS scale. Both were significantly elevated compared with the topical treatment group 6.1 ⫾ 0.716 SEM (P ⫽ .1057) (Fig. 1). Following treatment (i.e., at least 30% pain relief) (ANOVA for “pain after”: F ⫽ 1.204, P ⫽ .3117), pain level was significantly reduced in all 3 groups, although it was different for all 3 groups. The combined treatment group had the most relief of 52.0 ⫾ 6.676 SEM % pain reduction (from 7.5 to 3.6 on the VAS) (P ⬍ .0001). The systemic treatment group demonstrated 40.6 ⫾ 9.727 SEM % pain reduction (from 8.6 to 5.1 on the VAS) (P ⫽ .0029) and the topical treatment group demonstrated 40.9⫾ 10.775 SEM % pain reduction
OOOOE April 2008
Heir et al.
10 9 8 7 6 5 4 3 2 1 0
*
70 60
*
Combined Systemic Topicals
Percentage
VAS
468
50 Combined Systemic Topicals
40 30 20 10 0
Fig. 2. Percentage pain relief obtained. Pain Before Treatment
Pain Following Treatment
Pain levels before and following treatment.
Fig. 1. Pain levels before and following treatment.
Combined Systemic Topicals
7
(from 6.1 to 3.6 on the VAS) (P ⫽ .0048). ANOVA for “percentage relief”: F ⫽ 0.570, P ⫽ .5704 (Fig. 2). The time taken (ANOVA: F ⫽ 3.254, P ⫽ .0502) for the topical treatment to reduce pain was significantly shorter (3.000 ⫾ 0.479 weeks SEM; P ⫽ .0015) when compared with the systemic only group (4.000 ⫾ 0.772 weeks SEM; P ⫽ .3629) and the combined group (5.500 ⫾ 0.912 weeks SEM; P ⫽ .1738) (Fig. 3). DISCUSSION The most important finding of this study is that topical treatment may be effective in the treatment of neuropathic orofacial pain, since a 30% reduction in pain levels is considered a good response.16,17 Topical medications seem to have increased effectiveness when the starting pain levels were mild to moderate. In cases of severe pain, there was a reduced effect. We postulate that this may be because of limited patient compliance with the use of topical medications alone in such cases. Combination strategies may be effective in reducing the risk of adverse drug reaction, drug tolerance, or addiction.18-20 Currently drugs used to manage neuropathic pain improve mood and quality of life. They are limited by side effects. The potential for combination pharmacotherapy is being explored.19,20 However, as a retrospective evaluation, the data collection had certain limitations. The pain relief felt by the patients was based on their subjective feeling and was not standardized. The time point at which the data were collected was not the same for all the patients. Furthermore, there may have been variability in the number of times the topical medication was applied during the day, which could affect the pain relief obtained. The topical group had less pain initially, which could account for better pain relief obtained. The dosage of the systemic medication was not the same for all patients as it was adjusted based on the severity of the patient’s pain. Although the treatment offered was based on the sever-
Weeks
6 5
*
4 3 2 1 0 Time taken for pain relief.
Fig. 3. Time taken for pain relief.
ity of pain felt by the patient, it was not standardized, as each group had different diagnoses and it would have complicated the results to analyze each group separately. Since the number of patients in each group was small, this could have reduced the power of the study. Despite possible shortcomings, this study does seem to indicate that topical delivery of medications to a painful treatment target represents a unique means by which to accomplish a local pharmacotherapeutic action.18,21 The topical medication can be ordered from a compounding pharmacy where it can be formulated to contain carbamazepine 4%, lidocaine 1%, ketoprofen 4%, ketamine 4%, and gabapentin 4%. Carbamazepine and gabapentin, which are anticonvulsant drugs, act by suppressing paroxysmal discharges and reducing neuronal hyperexcitability.22 Lidocaine, which is a local anesthetic, acts by blocking sodium channels, preventing nerve depolarization.23 Ketoprofen has anti-inflammatory activity.24 Last, ketamine blocks N-methyl-D-aspartate (NMDA) receptors, whose hyperactivity contributes to maintenance of neuropathic pain.25 The topical should have penetration enhancers such as anhydrous gels and bio-adhesive copolymers. These are used to carry the medication transdermally and transmucosally.26,27 The anhydrous gel base is composed of propylene glycol (PG), glycerin, and ethoxy diglycol (EG) in varying percentages depending on depth of penetration desired.
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Anhydrous gels via micelle and solubilization of oils and water activate chemicals that can penetrate the epidermis, which is lipid in nature. The solubilizing power of EG was found to be valuable for increasing the concentration gradient in the skin. It is also possible to modulate the depth of drug delivery.28-30 Increasing the concentration of EG limits the penetration depth of the gel. This “shallow” penetration is advantageous in targeting more superficial nerve endings in the dermal layer. In the clinical setting, this would be useful if a patient has a traumatic neuroma, area of deafferentation, or an intraoral trigger zone in cases of trigeminal neuralgia. A neurosensory stent can be fabricated to prevent the medication from being washed away by saliva. The patient can be asked to apply the topical medication in the affected area several times a day. This can potentially help patients who are intolerant of systemic medications, older patients,8 and medically compromised patients. Pain signaling involves complex mechanisms. For neuropathic pain, peripheral activity of afferent nerves is an important contributor to pain. These conditions can benefit from a localized application of topical medications31; combinations of agents targeting different pain mechanisms may be particularly useful. It is postulated31 that topical medications may play a role in desensitizing trigger zones and can reduce the peripheral sensibility of areas affected by deafferentation and neuroma formation. CONCLUSION Topical medications can provide rapid pain relief either alone or in combination with systemic medication. The effectiveness, indication, dosage, and components are still open to discussion. This pilot study can serve as the basis for further prospective studies on the subject. REFERENCES 1. Merskey H, Bogduk N, International Association for the Study of Pain. IPT, Classification of Chronic Pain, 2nd ed. IASP Task Force on Taxonomy. Seattle (WA): IASP Press; 1994. pp. 209-14. 2. Truelove E. Management issues of neuropathic trigeminal pain from a dental perspective. J Orofac Pain 2004;18(4):374-80. 3. Vickers ER, Cousins MJ. Neuropathic orofacial pain, part 1—prevalence and pathophysiology. Aust Endod J 2000;26(1):19-26. 4. Delcanho RE. Neuropathic implications of prosthodontic treatment. J Prosthet Dent 1995;73(2):146-52. 5. Gregg JM. Neuropathic complications of mandibular implant surgery: review and case presentations. Ann R Australas Coll Dent Surg 2000;15:176-80. 6. Lewis MA, Sankar V, De Laat A, Benoliel R. Management of neuropathic orofacial pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(Suppl):S32 e1-24. 7. Watson CP. Management issues of neuropathic trigeminal pain from a medical perspective. J Orofac Pain 2004;18(4):366-73. 8. Feinberg SD. Prescribing analgesics. How to improve function and avoid toxicity when treating chronic pain. Geriatrics 2000;55(11):44-62. 9. Collins SD, Chessell IP. Emerging therapies for neuropathic pain. Expert Opin Emerg Drugs 2005;10(1):95-108.
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