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Year : 2009  |  Volume : 20  |  Issue : 1  |  Page : 3-6
Evaluation of the effect of locally administered amitriptyline gel as adjunct to local anesthetics in irreversible pulpitis pain

1 Department of Pharmacology, Babol University of Medical Sciences, Babol, Iran
2 Department of Endodontics, Babol University of Medical Sciences, Babol, Iran
3 Faculty of Dentistry, Babol University of Medical Sciences, Babol, Iran

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Date of Submission26-Feb-2007
Date of Decision25-Apr-2008
Date of Acceptance27-Aug-2008


Background: Amitriptyline is one of the most common tricyclic antidepressants, which binds to pain sensory nerve fibers close to the sodium channel; hence, it could interact to some degree with receptors of local anesthetics. This study was designed to assess the additional analgesic effects of 2% Amitriptyline local gel administration in irreversible pulpitis pain of the molars.
Materials and Methods: This study was a randomized, double-blind clinical trial that was performed on 56 consented adult patients who did not receive enough analgesia after a lidocaine nerve block for their tooth pulpitis pain. Patients were treated with 0.2 ml of either 2% amitriptyline or placebo, which was directly injected into their mandibular molar pulp chamber after they had received two routine lidocaine injections. Patients were asked to score their pain as a mark on a 10-cm Visual Analogue Scale (VAS) at different timepoints: 0 (just before gel administration), 1, 3, 5, 7, and 9 minutes after the treatments.
Results: There was a 92.5% decrease in VAS scores of patients 9 minutes after amitriptyline administration compared to Time 0, while in the placebo group this difference was only 13.5%. Further, in the amitriptyline group, the VAS score at all timepoints was statistically different from Time 0 ( P <0.01). The overall pain reduction and its trend was significantly higher in the amitriptyline group compared with the placebo group ( P <0.001).
Conclusion: Inter-pulp space administration of amitriptyline 2% gel for completing analgesia in irreversible pulpitis pain could be effective and useful as a conjunctive therapy to injections of local anesthetics.

Keywords: Amitriptyline, endodentics, irreversible pulpitis, local anesthesia, tricyclic antidepressants

How to cite this article:
Moghadamnia A A, Partovi M, Mohammadianfar I, Madani Z, Zabihi E, Hamidi M R, Baradaran M. Evaluation of the effect of locally administered amitriptyline gel as adjunct to local anesthetics in irreversible pulpitis pain. Indian J Dent Res 2009;20:3-6

How to cite this URL:
Moghadamnia A A, Partovi M, Mohammadianfar I, Madani Z, Zabihi E, Hamidi M R, Baradaran M. Evaluation of the effect of locally administered amitriptyline gel as adjunct to local anesthetics in irreversible pulpitis pain. Indian J Dent Res [serial online] 2009 [cited 2023 Mar 20];20:3-6. Available from:
Failure to achieve anesthesia can be a significant problem in the practice of dentistry. Studies show that more than 50% of U.S. adults miss dentistry services because of a fear of pain. [1] Controlling patients' anxiety and distress, good treatment of root canals, effective use of local anesthetics, and drug therapy cover the main factors in the management of dental pain. [2] Sometimes, pH changes associated with peri-apical inflammation or infection make it hard or even impossible to achieve a deep local anesthesia of the pulp. [1],[3] One of the most difficult situations to achieve profound anesthesia is in the mandibular molar with acute pulpitis in which the local anesthetics are delivered some distance away from the inflammation. One way to anesthetize the acutely inflamed tooth is to use supplemental injection techniques such as an intrapulpal injection. [4] Intrapulpal injections involve anesthesia of the nerve within the pulp canal of the individual tooth to be treated. When pain control cannot be achieved by any of the routine methods, the intrapulpal method may be used once the pulp chamber is open. [5]

In these cases, additional completing actions like local anesthetic (LA) injection into the pulp space, exposed by caries or by a high speed bur is usually applied. [1],[3] There are some studies that indicate that tricyclic antidepressants (TCAs) are effective for controlling neuropathic pain, which is unrelated to their antidepressant properties. [6],[7] Orally administered amitriptyline has shown this analgesic property in neuropathic pain. [8],[9],[10] TCAs possess a wide range of peripheral and central activities including analgesia. [11] Amitriptyline and desipramine have shown analgesic properties in formalin test pain models in rats. [11],[12] It seems that the amitriptyline analgesic effect is partly mediated by adenosine receptors. [13] On the other hand, it has been shown that TCAs could interact with Na-channel on sensoryness in a very similar way to the local anesthetics mechanism of action [14] and doxepin (a TCA derivative) has analgesic properties when administered topically. [15] Based on this similarity between LAs and TCAs, this study was designed to evaluate amitriptyline efficacy in resistant tooth pain (including peri-apical pain in which LAs do not produce a sufficient level of pain control.

   Materials and Methods Top

This study was performed as a double-blind clinical trial and all patients who underwent the study had been fully informed and given written consent for the study procedure and its design.

Patient Selection (Inclusion and Exclusion Criteria)

All 19 to 42 year old patients who did not have any systemic diseases, suffered from severe pain and felt moderate to severe pain in one of their mandibular molars, which had not been completely relieved by local anesthetic administration during preparation of access cavity, were selected for the study. All subjects with irreversible pulpitis were selected based on clinical examination. In the examination, teeth that are characterized as having symptomatic irreversible pulpitis exhibit intermittent or spontaneous pain, whereby rapid exposure to dramatic temperature changes (especially to cold stimuli) will elicit heightened and prolonged episodes of pain even after the source of the pain is removed.

Patients with a history of hypersensitivity to TCAs, epinephrine, or lidocaine were excluded from the study. Furthermore, pregnant or lactating patients who had received systemic analgesics 4 to 6 hours prior to the surgery were excluded from the study.


Amitriptyline (Daru-pakhsh, Iran), CMC (Merck, Germany), Tragacant (Local shops, Babol, Iran) were purchased and used to make the vehicle gel or 2% amitriptyline gel in the Department of Pharmacology.


Patients who had tooth pain during the preparation of access cavity after the nerve block method by a maximum of two injections of two carpools of lidocaine 2% (containing 1/80000 epinephrine) were included in the study. If the pulp chamber was not exposed, it was opened by a "High-Speed Diamond Bur" in one point then all of the patients were asked to fill out a VAS pain assessment form. This standard form consists of a 10 cm ruler diagram that patients need to score their pain (0 = no pain; 10 = highest intolerable pain) at 0 (just before treatment), 1, 3, 5, 7, and 9 minutes after gel administration. Patients were asked to score their pain on an ordinal scale (no pain, mild, moderate, and severe pain) as well. After pain scoring at Time 0, patients were divided into two groups and each group received 0.2 ml of either placebo (gel vehicle only) or amitriptyline 2% gel injected into the pulp cavity space using a special blunt syringe. The gels were administered based on a double-blind method. The patients' pain scores were obtained using VAS forms and self-scoring at different timepoints soon after touching the pulp cavity with an explorer. Meanwhile, any undesirable symptoms or side effects were recorded.

Data Analysis

The mean ± SD scores on the VAS at the beginning (Time 0) and at different timepoints were calculated. The Mann-Whitney test was used to compare between the two groups at different timepoints to find any significant differences in VAS scores. Also, the 'Repeated Measure' test was used for inter-groups data at different timepoints. Any difference with P<0.05 was considered significant.

   Results Top

From 56 patients who finished the study, 27 had been treated with amitriptyline. The mean±SD age range of patients was 27.75±8.5 (with a range of 15 to 49) for the amitriptyline group and 27.79±7.73 (14 to 48) for the placebo group. As shown in [Table 1] and [Figure 1], there was no significant difference in VAS between the placebo and amitriptyline groups at the beginning of the experiment (Time 0). There was a significant (92.5%) decrease in the pain score in the amitriptyline group at Time 9 (VAS= 0.65±0.44) compared with Time 0 (VAS=8.72±0.68) (P<0.05). These results are shown in a different theme in [Figure 1]. On the other hand, for the placebo group, VAS scores at Time 9 (7.53±1.05) had only a 13.5% decrease compared with Time 0 (8.72±0.9), which is not statistically significant [Table 1]; [Figure 1]. An inter-group comparison for amitriptyline at different timepoints showed significant decreases in pain scores (P<0.05). However, this comparison of VAS scores at different timepoints in the placebo group only showed significant decreases between Times 0 against 5, 0 against 7, and 0 against 9. For the other timepoints, there were no significant differences in VAS scores. Furthermore, using the Repeated Measure test it could be presented that there is a significant difference of VAS scores trends in the two groups (P<0.0001). Also, the trend in therapeutic effects in two treatment groups (placebo and amitriptyline) was obtained, which are depicted in [Figure 1]. Pain VAS scores at each timepoint is compared with Time 0, and their corresponding combined bar chart at different timepoints (compared with Time 0) are depicted in [Figure 1]. A decreased trend in the severity of pain could be observed in the amitriptyline group at different timepoints.

   Discussion Top

Despite TCAs that have been successfully used in some types of neuropathic pain, and their efficacy in blocking Na-Channels in the nervous system, [7,15] they have not been used systemically for the completion of anesthesia in dental pain because of their potential risk of producing many adverse drug reactions. However, topical use of a lipid soluble TCA, e.g., amitriptyline, directly administered into the pulp cavity of a painful tooth in addition to routine local anesthetic injections may synergistically complete analgesia through co-inhibition of Na-Channels on pain sensory fibers. The obtained results from this study show that local administration of amitriptyline has complementary analgesic effects on local anesthesia induced by lidocaine. Local administration of amitriptyline significantly reduces the risk of its systemic side effects while it could proficiently complete the analgesic effects of local anesthetics in patients with irreversible pulpitis pain. Usually, narcotic analgesics (e.g., morphine) have been used to control this type of pain. Morphine and other related narcotics fulfill their completing analgesic effects by affecting the opioid receptors predominantly located in the central nervous system (CNS). Furthermore, amitriptyline, orally administered 90 minutes before dental surgery, has shown to complete analgesic activity. This analgesic effect has been suggested to be partly mediated by enkephalin pathways in the CNS. [14],[16],[17],[18] This CNS effect of amitriptyline has made it a useful analgesic remedy for neuropathic pain; for example, in herpes zoster infection and in conjunction with other drugs in mouth burn syndrome. [14],[19],[20],[21] The proposed mechanism for amitriptyline analgesic activity in these neuropathic pains is its effect on serotoninergic descending pathways in spinal dorsal horns and enkephalin neurotransmission pathways. [17],[18]

Analgesic activity of amitriptyline is more likely to be peripheral than central for a few reasons. Firstly, its onset of action is very rapid (i.e., within 9 minutes); secondly, the small dose of amitriptyline used is unlikely to reach plasma therapeutic levels; and thirdly, absorption from the pulp cavity space into the systemic circulation is generally poor. These two restrictions are the main reasons to assume that amitriptyline analgesic activity has just mediated through local effects. Although this local analgesic effect is similar to capcisine, which affects C-fibers of pain sensory pathways, [16] their mechanisms of action seem to be different. Studies have revealed that amitriptyline has special binding sites on nerve fibers close to local anesthetics receptors on Na-channels; [15],[22] hence, it is very likely that this local analgesic activity might have been mediated by interaction with these receptors. In other words, since the amitriptyline binding site on pain fibers might be the same or located very close to the local anesthetics receptive sites, it could potentiate local anesthetic effects.

Amitriptyline local anesthetic activity might be partly mediated by increasing the pressure induced by gel injection into pulp space, which has a small restricted volume. Previous studies have shown that increasing inter pulp pressure by injection directly into the pulp cavity space increases anesthetic activity and induces better pain control. [23] However, as a gel vehicle had been used as placebo, the main mechanism of analgesic action of amitriptyline seems to be its Na-channels blocking property. Blocking Na-Channels in the neurons and consequently decreasing action potential, inhibition of EPSP, and finally blocking the pain pathway would be expected. [15] It seems that this Na-channel inhibition increases by time as it peaks at Times 7 and 9 minutes after injection, which is in agreement with other studies, i.e., Khan, who showed amitriptyline has a longer Na-channel inhibition than bupivacaine. [24]

This relatively longer duration of action helps the dentist to have enough time to extract the pulp content precisely. [23] On the other hand, Estebe, et al. showed that murine syatic nerve long-term exposure to amitriptyline might exhibit neurotoxicity and lead to peripheral neuropathy. [25] It should be noticed that for this potential of neurotoxicity and other probable side effects, amitriptyline should not be administered at high doses or for a long term. However, as the pulp content would be extracted, this neurotoxicity does not seem to be an important problem in the local use of amitriptyline. On the other hand, the total amount of amitriptyline administered as local gel is 0.4 mg, which is less than the reported minimum neurotoxic dose (0.6 mg). [25]

In conclusion, amitriptyline local gel seems to be effective as a conjunctive therapeutic agent to local anesthetics for completing their analgesic activity in irreversible pulpitis pain. This fortifies dentists with a better level of pain control and time margin for endodentics procedures.

   References Top

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Correspondence Address:
A A Moghadamnia
Department of Pharmacology, Babol University of Medical Sciences, Babol
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-9290.49047

Clinical trial registration None

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