New Findings on Local Tramadol Use in Oral Surgery.

In modern times, all procedures in oral surgery need to be painless and management of postoperative pain needs to be adequate. The surgical extraction of the third molar or alveolectomy of the wisdom tooth is one of the most common surgical procedures carried out in oral surgery and it includes rising a flap, bone removal and suturing. These surgical procedures usually cause swelling, trismus and moderate to severe pain. Third molar surgery is often used as a model in clinical trials that are directed toward reducing postoperative pain and improving its management. Tramadol is a well-known central acting opioid analgesic that produces analgesia against multiple pain conditions such as postsurgical pain, obstetric pain, terminal cancer pain, pain of coronary origin and neuropathic pain. Tramadol is an atypical opioid. When administered locally, it has both analgesic and anesthetic properties. The aim of this paper was to present new findings on local effects of tramadol in oral surgery.

Introduction:

Pain control in oral surgery is a key factor for reducing fear and anxiety in patients. Improved postoperative pain management after oral surgery may lead to faster recovery in terms of lifestyle and oral function (, ). Pain management is usually based on different analgesic medications that can be divided into three major drug classes: non-opioid drugs [non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), metamizol], opioids and adjuvants (antidepressants, anticonvulsants and local anesthetics). The choice of analgesic drug is as important as the route of administration for a drug. The various routes of administrations are classified into following categories: enteral (sublingual, peroral and rectal) and parenteral (intravascular, intramuscular, subcutaneous and inhalation). Also, time of administration of an analgesic drug plays important role in pain management and it can be preoperative, intraoperative and postoperative. A great deal of attention has recently been directed at combining analgesic drugs (multimodal analgesia) or combining different routes of administration of the same drug (e.g. locally at the site of tissue injury and systemically). Targeting both peripheral and central pain pathways enables to maximize the analgesic effect by using lower doses of drugs and thereby lowering the risk of adverse events. Over the past few years, years there has been a significant increase in the use of local anesthetic peripheral nerve blocks for surgical anesthesia and postoperative analgesia. Adjuvants are frequently added to local anesthetics to enhance the quality and duration of the anesthetic effect, and also to improve postoperative analgesia. A number of clinical trials have investigated the effects of some adjuvants such as: buprenorphine, morphine, fentanyl, epinephrine, clonidine, dexmedetomidine, dexamethasone, tramadol, and magnesium ().

Tramadol hydrochloride [(1RS; 2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] is a centrally acting weak opioid analgesic clinically effective in treating moderate to moderately severe pain. This drug was first synthetized back in 1962, but has not been commercially available until 1977. The main action mechanisms of tramadol are μ-opioid receptors (μ-OR) agonism and inhibition of the monoamine reuptake (). Commercially, tramadol comes as a racemic mixture of two enantiomers (+) tramadol and (-) tramadol that has superior analgesic properties than either enantiomer alone (). In comparison to codeine and morphine, tramadol has a very low affinity for the μ-OR and this affinity is estimated to be 10 times lower than that of codeine and 6000 times lower than that of morphine. Tramadol analgesic/opioid action via μ-OR alone is insufficient to represent its analgesic properties (, ). There are twenty-three metabolites of tramadol identified as a result of demethylation, oxidation and conjugation (sulphation and glucuronidation) in the liver (, ). O-desmethyl tramadol (M1) is the main metabolite of tramadol, and its affinity toward μ-OR is approximately 300-fold higher than that of the parent compound. Nevertheless, its affinity is still lower than that of morphine (, ). Non opioid analgesic action mechanism of tramadol had been identified via inhibition of the reuptake of monoamines, such as norepinephrine (NE) and serotonin [5-hydroxytryptamine (5-HT)] that are released from nerve endings. By inhibition of the reuptake of monoamines, tramadol is inhibiting pain transmission in the central nervous system, and in this way contributing to its analgesic effect (). Enantiomer (+) tramadol is primarily responsible for serotonin reuptake inhibition, (-) tramadol for noradrenaline reuptake inhibition and the metabolite O-desmethyltramadol (M1) is primarily responsible for the agonist activity on the μ-opioid receptor. Recent studies focused on ion channels and G protein-coupled receptor (GPCR) signalling, thus improving our understanding of their physiology and pharmacology. Moreover, it has been discovered that they are also targets for analgesics and anesthetics. Apart from the two main described mechanisms of tramadol action, we do not yet know additional mechanisms of tramadol action ().

Unfortunately, there is an increase in the unjustified use of opioid analgesic drugs in dentistry, especially in oral surgery, prescribed for pain management after tooth extraction or third molar surgery. In 2015 in the United States of America (USA), there were more than 52 404 deaths due to drug overdose, out of which 63.1% were from opiate and opioid drugs (). In scientific and medical associations in the USA there are more and more discussions on the topic of opioid epidemic and its control. It is estimated that patients’ expectations to receive opioid analgesic after dental treatment and dentists’ fear of an unsatisfied patient are the main causes for opioid analgesic prescription (). A disturbing fact is that the USA consumes 99% of the world’s hydrocodone/acetaminophen combination (). The first experience of a large number of patients with opioids is associated with dental procedures, such as extractions of wisdom teeth. It has been estimated that almost two-thirds of 14 to 17-year-olds receive opioid prescriptions from dentists following the third molar extraction (). In Europe, the medical use of prescription opioids is also increasing, but at a much slower rate than in the USA. Moreover, non-medical use of prescription opioids and fatal prescription opioid incidents are (still) rare in Europe (). Traditionally, in the USA, oral health professionals have been taught that nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol) should be used for mild to moderate pain, and opioids should be prescribed for severe pain. There is, however, no scientific evidence to support this recommendation (). In fact, the evidence shows that NSAIDs alone or in combination with acetaminophen are more effective than opioids or their combination administrated systemically in treating dental pain (-). In a systematic review and meta-analysis of analgesic efficiency of tramadol compared to NSAID administered systemically, the researchers have concluded that tramadol alone or in combination with acetaminophen has weaker analgesic effect compared to acetaminophen and ibuprofen (-). Also, the results of some studies have pointed to the fact that tramadol had an increased risk of adverse effects such as nausea, vomiting and dizziness. Opioid analgesics are not more effective in pain management after tooth extraction or third molar surgery when compared to NSAIDs. The recommendation to dental professionals is to prescribe NSAIDs for dental pain relief, and in a case of severe pain, to prescribe a combination of NSAIDs and paracetamol. However, opioids can be considered a first-line option for patients who are intolerant to NSAIDs or those with some contraindications, such as allergy, renal failure and high-risk of gastrointestinal hemorrhage.

Local action mechanisms of tramadol:

Research has tended to focus on local mechanisms of action of tramadol. Tramadol is an atypical opioid and its local mechanisms of action have not yet been fully elucidated. The local anaesthetic effects of tramadol are as follows: anesthetic and opioid/analgesic (). Studies have shown the following possible local mechanisms of action of tramadol:

weak peripheral agonism over peripheral μ-OR (, ), the number of which is enhanced in hyperalgesic and inflammatory conditions (, )

favouring the opening of nonspecific voltage-dependent potassium (K+) channels ()

acting in the nitric oxide pathway ()

agonistic action on vanilloid receptor 1 (TRPV-1 transient receptor potential vanilloid-1) that apart from local analgesic effect, can exert undesired local side effects, such as burning pain and erythema ()

with high concentration of tramadol blockade of the N-methyl-D-aspartate (NMDA) receptors ()

local anesthetic effect of tramadol can be explained by direct blocking of voltage-dependent sodium (Na+) channels ()

In 1998, Pang et al. were the first to demonstrate a local analgesic effect of tramadol following intradermal injection (). Tsai et al. demonstrated anesthetic effect of tramadol by its direct application on sciatic nerves of rats. Tramadol produced a neural conduction block that could not be reversed by naloxone. This finding suggested that an underlying mechanism of action of tramadol must differ from its opioid action (). Similar results have been reported by Mert et al. They have compared anesthetic effect of tramadol with local anesthetic on frog sciatic nerves. Nerve conduction blockade with tramadol was similar to that of lidocaine, although it was weaker. In conclusion, the authors have stated that tramadol could have different binding sites or different action mechanism than lidocaine (). Altunkaya et al. in theirs studies concluded that 5% tramadol has a local anesthetic effect similar to 2% prilocaine when used intradermally for excision of cutaneous lesions. Furthermore, they suggested that tramadol extends postoperative pain free time and reduces analgesic consumption (, ). Local anesthetic effect of tramadol was also demonstrated by Kargi et al. in tendon repair surgery of the hand, where tramadol was used as a local anesthetic (, ). Submucosal administration of tramadol after paediatric tonsillectomy surgery in general aesthesia has reduced the need for postsurgical analgesia (). Tramadol as an adjuvant to mepivacaine for axillary brachial plexus block prolongs the duration of aesthesia and depending on the dosage improves postoperative analgesia (, ).

Local effects of tramadol in oral surgery:

Only few studies have investigated the local effects of tramadol in oral surgery (Table 1). In 2006, Pozos et al. conducted a study to evaluate the effects of tramadol added to articaine on aesthesia duration in mandibular third molar surgery. Tramadol (50 mg) was added to 4% articaine with epinephrine (1:100,000), and injected into surgical site into the buccal mucosa, adjacent to extraction wound, immediately after the inferior alveolar nerve block. The authors reported that they did not notice any local harmful effect of tramadol as an adjuvant to articaine at the site of application. In this study, the authors demonstrated that tramadol injected submucosally next to the extraction socket prolongs the anesthetic effect of articaine and that such administration could improve the management of postoperative pain (). In 2007, the same authors published a paper in which they evaluated the effects of tramadol administered systemically (intramuscular) and locally (submucosal) on reducing pain after the removal of an impacted mandibular third molar. The results showed that tramadol (50 mg) administered locally into the surgical site significantly prolonged the duration of the anesthetic effect (articaine) and when used in combination of routes (locally and systemically), improved the quality of postoperative analgesia. Tramadol administered through both routes resulted in an improved analgesic effect not only compared to control group but also compared to both systemic and local groups. In order to examine the fact that better analgesia was not the result of doubled drug dosage, the authors have measured tramadol plasma levels when administered locally by liquid chromatography. As tramadol levels were unmeasurable in plasma, the authors suggested that improved analgesia, as a result of tramadol administered in combination of routes could be a result of different pharmacodynamic mechanisms (). Isiordia-Espinoza et al. investigated the preemptive analgesic effectiveness of oral ketorolac (given orally 30 minutes before surgery) and local tramadol (submucosal) in mandibular third molar surgery. They have concluded that preemtive ketorolac plus submucosal local tramadol resulted in better postoperative treatment of acute pain and in reduction in the consumption of postoperative analgesics (). In a crossover clinical trial, the effect of submucosal tramadol as an adjuvant of 2% mepivacaine with epinephrine in inferior alveolar nerve block was evaluated. The submucous administration of tramadol was performed 1 minute after the patient had made informed decision about anesthesia of the lower lip. It was administered in the same manner as anesthetic block. In this study, submucous administration of tramadol was not applied into the surgical site, as it was the case with previous studies. The authors have concluded that tramadol applied submucosally in this manner increased the anesthetic efficacy of mepivacaine during the first 2 hours without affecting the onset of anesthesia (latency time), and without prolonging the duration of anesthesia of soft tissues (). Ceccheti et al. have investigated analgesic and the adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery. Tramadol was injected into the buccal mucosa adjacent to the third molar alveolus, immediately after extraction. They concluded that submucosal administration of tramadol contributed to providing a pain free period of 3.5-4 hours after extraction, with rare adverse effects and good patient acceptance. Nevertheless, no beneficial effect of tramadol in lengthening the sensory blockade produced with 2% mepivacaine was observed (). A similar investigation was conducted by Gönül et al. in which they applied tramadol (1 mg/kg) after mandibular third molar extraction to the extraction socket and the bone surface topically in small drops. An inferior alveolar nerve block was obtained using 4% articaine with epinephrine. From the mean weight of the patients included in the study, it can be concluded that the average tramadol dosage was 65 mg. The authors concluded that postsurgical pain VAS scores were significantly lower in first 12 hours, first analgesic intake was significantly later, and total analgesic intake was significantly lower, in the tramadol group compared to the control groups (). A very interesting study was conducted by Al-Haideri in which he investigated and compared local anesthetic efficacy of tramadol with adrenaline versus plain tramadol in the extraction of maxillary molar teeth. He concluded that tramadol with adrenaline injected supraperiosteally proved to be an effective local anesthetic for the extraction of upper molar teeth. Due to weak local anesthesia of plain tramadol (without adrenaline), the author stated that the presence of adrenaline, which produces vasoconstriction, thus deterring tramadol locally, is crucial for producing its anesthetic effects on the nerve. It was also highlighted that the study involved minor oral and maxillofacial surgery (teeth extraction). Although statistically non-significant (4% overall), the side effects of tramadol (nausea and vomiting) could limit the clinical use of this drug as a local anesthetic ().

Table 1

Studies of local administration of tramadol in oral surgery

Study	Routh of administration	Groups	Adverse events	Results
Pozos et al., 2006 (41)The effects of tramadol added to articaine on anesthesia duration	Tramadol added to 4% articaine with epi. (1:100 000) injected into surgical site into the buccal mucosa adjacent to the extraction	Tram 50mg (1 ml) + articaine (2.7 ml) n=24SA (1ml) + artikain (2.7 ml) n=24	Tramadol: nausea n=3Control:nausea n=2	prolongs the effect of local anesthetic articaineno difference between 2 groups for pain intensity value
Pozos et al., 2007 (42)Tramadol administered in a combination of routes for reducing pain after removal of an impacted mandibular third molar	Tramadol administered i.m. 1 hour befor surgery, and tramadol injected into surgical site submucous after IAN block obtained using 4% articaine with epi. (1:100 000)	Tram 50mg i.m. + SA 1 ml subm n=12SA i.m. + tram 50mg subm n=12Tram 50mg i.m. + tram 50mg subm n=12SA i.m. + SA 1ml subm n=12	Adverse events such as drowsiness, diziness and nausea were reported equally across the treamtent groups	Locally injected prolongs the effect of local anesthetic articaineIn combination of routes (local and sistemic) improves the quality of postoperative analgesia
Isiordia-Espinoza et al., 2011 (43)Preemptive analgesic effectiveness of oral ketorolac plus local tramadol after impacted mandibular third molar surgery	Ketorlac per os 10 mg 30 minutes before surgery + tramadol 50 mg injected into surgical site submucous after IAN block obtained using 4% articaine with epi. (1:100 000)	Ketorlac 10 mg per os + SA 1ml subm n=15Ketorlac 10 mg per os + tram 50 mg subm n= 15	No patients reported adverse events	Ketorlac per os plus local tramadol resulted in better postoperative pain management and reduced analgesic consumption
Isiordia-Espinoza et al., 2012 (44)Submucous tramadol increases the anesthetic efficacy of mepivacaine with epinephrine in inferior alveolar nerve block.	submucous administration of tramadol was done 1 minute after that patient informed anesthesia of lower lip in the same way as was done anesthetic IAN block using 2% mepivacaine with epi (1:100 000)	Tram 50 mg 1 ml n=20SA 1 ml n=20	Tramadol: dizziness n=2 nausea n=1 dizziness and nausea n=2Placebo: dizziness n=1 dizziness and nausea n=1	Increased anesthetic efficancy of mepivacaine withough prolonging the duration of anesthesia of soft tissue nor affecting the onset of anesthesia
Ceccheti et al., 2014 (45)Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery	tramadol was injected into the buccal mucosa adjacent to the third molar alveolus immediately after extraction;IAN block done using 2% mepivakain with levonorfedrinom (1:80 000)	Tram 100 mg 2 ml n=52SA 2 ml n=52	Tramadol: dizziness and nausea n=3Control: dizziness and nausea n=1	Contributes to provide a pain-free postoperative period of 3.5-4 h with no effect in leghtening the sensory blockade produced with mepivacaine
Gonul et al., 2015 (46)Effect of submucosal application of tramadol on postoperative pain after third molar surgery	tramadol (1 mg/kg) was applied after extraction to the extraction socket and the bone surface by means of small drops;IAN block was obtained using 4% articaine with epinephrine (1:100 000)	Tram 1mg/kg diluted with SA do 2 ml n=30SA 2 ml n=30	Tramadol: nausea n=5Control:nausea n=2 vomiting n=2 burning n=3	Reduces postoperative acute facial pain
Al-Haideri, 2013 (47)Comparison of local anesthetic efficacy of tramadol hydrochloride (with adrenaline) versus plain tramadol hydrochloride in the extraction of upper molar teeth	tramadol is injected supraperiosteally as a local anestethic	Tram 50 mg with adrenaline (1:80 000) n=50Tram plain (without adrenaline) 50 mg n=50	Tram with adrenaline: nausea n=2 vomiting n=1Tram:nausea n=1	Tramadol with adrenaline was shown to be a very effective local anesthetic for extration of upper molar teeth

*epi-epinephrine; Tram-tramadol; SA-saline; i.m.-intramuscular; subm-submucosal; per os-peroral; IAN-inferior alveolar nerve

Conclusion:

The imperative of modern oral surgery is to ensure high quality local anesthesia and to adequately and efficiently control a patient's pain post operatively. A large number of studies and meta-analysis have shown NSAIDs advantages over systemically administrated opioid analgesics, and concluded that opioids should not be prescribed as the first line of pain control for treatment of acute dental pain. On the other side, local administration of atypical opioid tramadol opens new possibilities in postsurgical pain management, and an improvement in local anesthetics properties. In this regard, tramadol applied locally submucosally, supraperiosteally, topically by means of small drops or as an adjuvant to local anesthetic, could provide promising results. However, further studies are required to elucidate local mechanisms of action of tramadol. Furthermore, there is a need for large clinical studies to investigate safe and effective protocols for local administration of tramadol in everyday practices.