. 2018 Dec 28;18(6):319–332. doi: 10.17245/jdapm.2018.18.6.319

Table 2. In vivo and in vitro papers included in this current review, indicating reference, year of publication, type of amides involved, type of anesthesia involved and conclusion of the study.

Authors, Country, Year	Type of study	Amid and Vasoconstrictor Concentrations	Technique Used: Block or Infiltration? Mandibular or Maxillary?	Number of Subjects in Study	Conclusion of Study
Colombini BL et al. Brazil, 2006 [45]	randomised double blind cross-over study	• 4% articaine and 1:100k epinephrine	Inferior alveolar nerve block (third molar removal)	20	Articaine provides a longer period of analgesic effect and a tendency for a longer period of anesthesia as compared to mepivacaine. The presence of a vasoconstrictor agent in local anesthetic solutions does not seem to influence hemodynamic parameters during lower third molar removal in healthy subjects.
Colombini BL et al. Brazil, 2006 [45]	randomised double blind cross-over study	• 2% mepivacaine and 1:100k epinephrine	Inferior alveolar nerve block (third molar removal)	20
Jain NK et al. India, 2016 [31]	comparative prospective	• 4% articaine and 1:100k epinephrine	Inferior alveolar nerve block (third molar surgical removal)	70	Results showed that 4% articaine had a significant faster onset and longer duration of action when compared to 2% lignocaine. We concluded that 4% articaine is a safe alternative to 2% lignocaine, which is potent and effective in minor surgical procedures such as removal of mandibular third molars.
Jain NK et al. India, 2016 [31]	comparative prospective	• 2% lignocaine and 1:80k epinephrine		70
Pellicer-Chover H et al. Spain, 2013 [46]	comparative split mouth	• 4% articaine and 1:100k epinephrine	Inferior alveolar nerve block (third molar surgical removal)	36	Articaine showed greater clinical efficacy than bupivacaine, reducing latency time, bleeding, anesthetic duration in the soft tissues and achieving higher anesthetic quality, requiring less reinforcement during surgery than bupivacaine.
Pellicer-Chover H et al. Spain, 2013 [46]	comparative split mouth	• 0.5% bupivacaine and 1:200k epinephrine		36
Budharapu A et al. India, 2015 [18]	randomised single blind trial	• 0.5% ropivacaine	Inferior alveolar nerve block (third molar surgical removal)	78	We had no adverse effects from 0.5% ropivacaine, which provided efficient anesthesia and excellent residual analgesia with no cardiovascular or central nervous system complications. The addition of adrenaline to ropivacaine has been shown not to improve the anesthetic effect and may cause transient increases in arterial pressure and heart rate. Evaluation of the plasma concentration would give more details about its effects on the cardiovascular system, as we confined ourselves to studying only the haemodynamic changes.
Budharapu A et al. India, 2015 [18]	randomised single blind trial	• 2% lignocaine		78
Brkovic BM et al. Serbia, 2010 [17]	double blind randomised controlled design	• 0.5% ropivacaine plain	infiltration (third molars maxilla)	66	In conclusion, the current data suggest that maxillary infiltration of 0.75 and 1% of ropivacaine offered adequate and safe intraoperative analgesia but not successful postoperative pain control for the surgical removal of upper third molars.
		• 0.75% ropivacaine plain
		• 1% ropivacaine plain
Christensen J et al. Denmark, 2013 [15]	randomised double blind cross over design	• 2% lidocaine with or without methylprednisolone or placebo	Inferior alveolar nerve block (third molar surgical removal)	126	Bupivacaine combined with methylprednisolone reduced the postoperative pain and swelling compared with the use of lidocaine and placebo, lidocaine and methylprednisolone, or bupivacaine and placebo. (two to four supplemental injections were administered sometimes)
Christensen J et al. Denmark, 2013 [15]	randomised double blind cross over design	• 0.5% bupivacaine with or without methylprednisolone or placebo		126
Krzeminski TF et al. Poland, 2011 [25]	randomised parallel group trial	• 0.5% ropivacaine plain	infiltration maxillary incisors and canines	60	The efficacy of anesthesia of lateral and central incisors was 100% for both anesthetics. There were insignificant differences in effectiveness of canine pulp anesthesia. Ropivacaine (0.5%) achieved effective and long duration of uninflamed pulp and soft tissue anesthesia. Ropivacaine could be useful for long-lasting operative procedures without the need for a vasoconstrictor.
Krzeminski TF et al. Poland, 2011 [25]	randomised parallel group trial	• 4% articaine and 1:100k epinephrine	infiltration maxillary incisors and canines	60
Thakare A et al. India, 2014 [47]	randomised cross-over study	• 4% articaine	infiltration in maxilla (premolar extractions)	40	The results showed that 4% articainehad significantly faster onset of action and lower VAS scores when compared with bupivacaine. However, the duration of analgesia and time to first rescue analgesic medication was longer in the bupivacaine group. Articaine seemed to have better potency and efficacy in terms of onset of action and lower pain scores compared to the bupivacaine group. Further studies are required to confirm these results. Moreover, the volume of LA required seemed to be lower in the articaine group, demonstrating better anesthetic potency and efficacy.
		• 0.5% bupivacaine
		• [epinephrine concentration unclear]
Ashraf H et al. Iran, 2013 [48]	randomised double blind study	• 2% lidocaine and 1:100k epinephrine	• Inferior alveolar nerve block	125	Supplementing an incomplete articaine inferior alveolar nerve block with articaine infiltration raises the anesthetic success more effectively compared with lidocaine in mandibular molars with irreversible pulpitis. The success rate after the administration of the infiltration injections after an incomplete inferior alveolar nerve blockby using lidocaine was 29%, whereas by using articaine it was 71%. No statistical differences were detected in the success rates between the 2 anesthetics after the block injections.
Ashraf H et al. Iran, 2013 [48]	randomised double blind study	• 4% articaine and 1:100k epinephrine	• infiltration	125
Brkovic B et al. Serbia, 2008 [49]	randomised double blind	• 2% lidocaine and clonidine (15ug/mL)	infiltration (maxilla)	40	The results of this study indicate for the first time in dental anesthesia that the lidocaine + clonidine combination could be a useful and safe alternative to lidocaine + epinephrine for intraoral infiltration anesthesia.
Brkovic B et al. Serbia, 2008 [49]	randomised double blind	• 2% lidocaine and epinephrine (12.5 ug/mL)	infiltration (maxilla)	40
Piccinni C et al. Italy, 2015 [16]	case-non-cas e study	unclear about concentrations of:	NA	17246	In conclusion, among local anesthetics, only articaine and prilocaine generated a signal of paresthesia, especially when used in dentistry. The highest number of reports was found for lidocaine (247 reports), followed by bupivacaine (99 reports), articaine (85 reports), combination of different local anesthetics (45 reports) and prilocaine (30 reports). A significant disproportionality of ‘paresthesias and dysaesthesias’ was found for articaine and prilocaine. Other local anesthetics did not show disproportionality signals according to the defined thresholds.
		• lidocaine
		• bupivacaine
		• articaine
		• prilocaine
Lammers E, et al. USA, 2014 [26]	prospective, randomised, double blind study	• 2% lidocaine with 1:100k epinephrine	Inferior alveolar nerve block	100	The combination of 3% mepivacaine plus 2% lidocaine with 1:100,000 epinephrine was equivalent to the combination of 2 cartridges of 2% lidocaine with 1:100,000 epinephrine in terms of injection pain, onset time, and pulpal anesthetic success for the IAN block.
Lammers E, et al. USA, 2014 [26]	prospective, randomised, double blind study	• 2% lidocaine with 1:100k epinephrine	Inferior alveolar nerve block	100
Visconti RP et al. Brasil, 2016 [13]	double blind randomised clinical trial	• 2% mepivacaine and 1:100k epinephrine	Inferior alveolar nerve block (irreversible pulpitis)	42	All patients tested reported lip anesthesia after application of either type of inferior alveolar nerve block. Pulpal anesthesia success rates measured by using the pulp tester were satisfactory for both solutions (86% for mepivacaine and 67% for lidocaine). Success rates according to patient report of no pain or mild pain during pulpectomy were higher for mepivacaine solution (55%) than for lidocaine solution (14%). The differences between mepivacaine and lidocaine were statistically significant. Mepivacaine resulted in effective pain
Visconti RP et al. Brasil, 2016 [13]	double blind randomised clinical trial	• 2% lidocaine and 1:100k epinephrine	Inferior alveolar nerve block (irreversible pulpitis)	42
Whitcomb M et al. USA, 2010 [32]	prospective, randomised, double blind	• 2% lidocaine and 1:100k epinephrine	Inferior alveolar nerve block	40	For the buffered 2% lidocaine with 1: 100,000 epinephrine/sodium bicarbonate formulation, successful pulpal anesthesia ranged from 10 to 71%. For the unbuffered 2% lidocaine with 1: 100,000 epinephrine formulation, successful pulpal anesthesia ranged from 10 to 72%. We concluded that buffering a 2% lidocaine with 1: 100,000 epinephrine with sodium bicarbonate, as was formulated in the current study, did not statistically increase anesthetic success, provide faster onset, or result in less pain of injection when compared with unbuffered 2% lidocaine with 1: 100,000 epinephrine for an IAN block.
Whitcomb M et al. USA, 2010 [32]	prospective, randomised, double blind	• 2% lidocaine buffered with sodium bicarbonate	Inferior alveolar nerve block	40
Kanaa MD et al. UK, 2012 [28]	randomised, double blind study	• 4% articaine and 1:1000k epinephrine	infiltration (maxilla and irreversible pulpitis)	100	There was no significant difference in efficacy between 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:80,000 epinephrine in achieving anesthesia in maxillary teeth with irreversible pulpitis after buccal infiltration.
Kanaa MD et al. UK, 2012 [28]	randomised, double blind study	• 2% lidocaine and 1:80k epinephrine	infiltration (maxilla and irreversible pulpitis)	100
Mohajeri L et al. Iran, 2015 [36]	randomised, double blind, clinical trial	• 2% lidocaine and 1:100k epinephrine with sterile distilled water	intraligamentary injections	60	Within the limitations of the present study, it appears that the addition of meperidine as an opioid to 2% lidocaine with 1 : 100,000 epinephrine will not improve the anesthetic efficacy of a periodontal ligament injection in patients with irreversible pulpitis for whom an inferior alveolar nerve block was ineffective despite lip numbness.
Mohajeri L et al. Iran, 2015 [36]	randomised, double blind, clinical trial	• 2% lidocaine and 1:100k epinephrine with 5% meperidine	intraligamentary injections	60
Gazal G, Saudi Arabia, 2017 [50]	randomised, double blind cross over study	• 4% articaine and 1:100k epinephrine	• Inferior alveolar nerve block	23	Articaine has better potency, rapid onset of action, earlier lip and teeth numbness compared to the mepivacaine group. Articaine/mepivacaine buccal injection was significantly more comfortable than mepivacaine inferior alveolar nerve block.
Gazal G, Saudi Arabia, 2017 [50]	randomised, double blind cross over study	• 2% mepivacaine and 1:100k epinephrine	• Buccal infiltration	23
Srinivasan N et al. India, 2009 [51]	prospective, randomised, double blind study	• 4% articaine and 1:100k epinephrine	infiltration (maxilla and irreversible pulpitis)	40	The success rate for maxillary buccal infiltration to produce pulpal anesthesia using articaine was 100% in first premolar and first molar, and for the lidocaine solution, success rate was 80% in first premolar and 30% in first molar.
Srinivasan N et al. India, 2009 [51]	prospective, randomised, double blind study	• 2% lidocaine and 1:100k epinephrine	infiltration (maxilla and irreversible pulpitis)	40
Glenn B et al. USA, 2016 [38]	prospective, randomised, double blind trial	• liposomal bupivacaine	• buccal infiltrations	100	The success rate was 29%for the liposomal group and 22% for the bupivacaine group, with no significant difference between the groups.
		• 0.5% bupivacaine and 1:200k epinephrine	• inferior alveolar nerve block
		• 2% lidocaine and 1:100 epinephrine	• infiltration (maxilla)
Schellenbe rg J et al. USA, 2015 [33]	prospective, randomised, double blind trial	• 4% articaine buffered with sodium bicarbonate and 1:100k epinephrine	Inferior alveolar nerve block	100	The success rate for the inferior alveolar nerve block was 32% for the buffered group and 40% for the non buffered group, with no significant difference between the groups.
Schellenbe rg J et al. USA, 2015 [33]	prospective, randomised, double blind trial	• 4% articaine and 1:100k epinephrine	Inferior alveolar nerve block	100
Shurtz R et al. USA, 2015 [34]	prospective, randomised, double blind trial	• 4% articaine buffered with sodium bicarbonate and 1:100k epinephrine	infiltration (mandible)	80	Buffered articaine did not provide any advantage over non buffered articaine for anesthetic success, anesthesia onset, or pain of injection for a primary buccal infiltration of the mandibular first molar.
Shurtz R et al. USA, 2015 [34]	prospective, randomised, double blind trial	• 4% articaine and 1:100k epinephrine	infiltration (mandible)	80
Nydegger B et al. USA, 2014 [52]	prospective, randomised, double blind trial	• 4% articaine and 1:100k epinephrine	infiltration (mandible)	60	The success rate for the 4% articaine formulation was 55%, 33% for the 4% lidocaine formulation, and 32% for the 4% prilocaine formulation. There was a significant difference between articaine and both lidocaine and prilocaine formulations.
		• 4% lidocaine and 1:100k epinephrine
		• 4% prilocaine 1:200k epinephrine
Rogers BS et al. USA, 2014 [53]	prospective, randomised, double blind trial	• 4% lidocaine and 1:100k epinephrine	• Inferior alveolar nerve block (irreversible pulpitis)	100	Seventy-four patients failed to achieve pulpal anesthesia after inferior alveolar nerve block with 4% articaine, resulting in inferior alveolar nerve block success rate of 26%. Success rates for supplemental buccal infiltrations were 62% for articaine and 37% for lidocaine, which was a significant statistical difference. This effect was most pronounced and significant in second molars.
Rogers BS et al. USA, 2014 [53]	prospective, randomised, double blind trial	• 2% lidocaine and 1:100k epinephrine	• Buccal infiltration	100
Cohen H et al. USA, 2013 [37]	prospective, randomised, single blind trial	• 1.72 mL 4% lidocaine and 50 ug/mL epinephrine	Inferior alveolar nerve block	40	We concluded that adding 0.9 M mannitol to a lidocaine with epinephrine formulation was significantly more effective in achieving a greater percentage of total pulpal anesthesia (as defined in this study) than a lidocaine formulation without mannitol. However, the 0.9 M mannitol/lidocaine formulation would not provide 100% pulpal anesthesia for all the mandibular teeth.
Cohen H et al. USA, 2013 [37]	prospective, randomised, single blind trial	• 5 mL 68.8 mg lidocaine with 50 ug epinephrine plus 0.9 M mannitol	Inferior alveolar nerve block	40
Martin M et al. USA, 2011 [29]	prospective, randomised, cross-over design	4% lidocaine and 1:100k epinephrine	infiltration (mandible)	86	The anesthetic efficacy of 3.6 mL 4% articaine with 1:100,000 epinephrine is better than 1.8 mL of the same anesthetic solution in a primary mandibular buccal infiltration of the first molar. However, the success rate of 70% is not high enough to support its use as a primary injection technique in the mandibular first molar.
McEntire M et al. USA, 2011 [54]	prospective, randomised, double blind cross-over trial	• 4% lidocaine and 1:200k epinephrine	infiltration (mandible)	86	The two 4% articaine formulations showed no statistically significant difference when comparing anesthetic success, onset of anesthesia, or incidence of pulpal anesthesia.
McEntire M et al. USA, 2011 [54]	prospective, randomised, double blind cross-over trial	• 4% lidocaine and 1:100k epinephrine	infiltration (mandible)	86
Wali M et al. USA, 2010 [55]	prospective, randomised, single blind trial	• 2% lidocaine and 1:50k epinephrine	Inferior alveolar nerve block	30	Increasing the epinephrine concentration to 1:50,000 epinephrine or increasing the volume to 3.6 mL of 2% lidocaine with 1:50,000 epinephrine did not result in more successful pulpal anesthesia when compared with 1.8 mL of 2% lidocaine with 1:100,000 epinephrine by using the inferior alveolar nerve block.
Wali M et al. USA, 2010 [55]	prospective, randomised, single blind trial	• 2% lidocaine and 1:100k epinephrine	Inferior alveolar nerve block	30
Goodman A et al. USA, 2006 [35]	prospective, randomised, single blind cross-over trial	• 4% lidocaine and 18 ug/ 1.8 mL epinephrine	Inferior alveolar nerve block	52	We conclude that the addition of meperidine to a standard lidocaine solution does not increase the success of the inferior alveolar nerve block.
Goodman A et al. USA, 2006 [35]	prospective, randomised, single blind cross-over trial	• 4% lidocaine and 36 ug/3.6 mL epinephrine and 36 mg meperidine	Inferior alveolar nerve block	52
Brunetto PC et al. Brasil, 2008 [30]	randomised, double blind cross-over study	2% lidocaine and 1:100k epinephrine	infiltration (maxilla)	25	It is concluded that maxillary infiltration anesthesia with lidocaine and epinephrine has a faster onset, a greater success rate, and a longer duration when a volume of 1.2 mL is used than when volumes less than 1.0 mL are used.
Poorni S et al. India, 2011 [20]	prospective randomised double blind clinical trial	• 4% articaine and 1:100k epinephrine	• Inferior alveolar nerve block	156	To summarize, on the basis of the results of the present study, it can be concluded that there is no statistically significant difference among inferior alveolar nerve block and infiltration of articaine when compared with inferior alveolar nerve block of lidocaine in mandibular molars with irreversible pulpitis. Hence compared with inferior alveolar block, buccal infiltration can be considered a viable alternative to secure pulpal anesthesia for endodontic therapy.
Poorni S et al. India, 2011 [20]	prospective randomised double blind clinical trial	• 2% lidocaine and 1:100k epinephrine	• infiltration (mandible)	156
Evans G et al. USA, 2008 [56]	prospective, randomised double blind study	• 4% articaine and 1:100k epinephrine	infiltrations (maxilla)	80	In conclusion, a maxillary infiltration of 4% articaine with 1:100,000 epinephrine statistically improved anesthetic success when compared with 2% lidocaine with 1:100,000 epinephrine in the lateral incisor but not in the first molar. Neither solution provided pulpal anesthesia for 1 hour.
Evans G et al. USA, 2008 [56]	prospective, randomised double blind study	• 2% lidocaine and 1:100k epinephrine	infiltrations (maxilla)	80
Sreekumar K et al. India, 2011 [27]	randomised double blind cross over study	4% articaine and 1:100k epinephrine	infiltration (maxilla)	10	Maxillary infiltration anesthesia with articaine and epinephrine has a faster onset, a greater success rate, and a longer duration when a volume of 1.2 mL is used than when volumes less than 1.0 mL are used. Palatal tissues were anesthetized with the highest concentration (1.2 mL) in our study (30% of cases).
Sampaio RM et al. Brasil, 2012 [21]	randomised double blind study	• 0.5% bupivacaine and 1:200k epinephrine	Inferior alveolar nerve block	70	Neither of the solutions resulted in an effective pain control during irreversible pulpitis treatments of mandibular molars. Before initiation of the pulpectomy procedure, 15 patients (42.9%) in the lidocaine group and 7 patients (20%) in the bupivacaine group exhibited pulpal anesthesia (ie, a negative response to electrical stimuli generated with an electric pulp tester). A significant difference between the 2 experimental groups for the pulpal anesthesia was observed, with more individuals in the lidocaine group presenting a negative response to electrical stimuli. During the pulpectomy, 7 patients in the bupivacaine group (20%) and 13 in the lidocaine group (37.1%) reported pain, however this difference was not statistically significant.
Sampaio RM et al. Brasil, 2012 [21]	randomised double blind study	• 2% lidocaine and 1:100k epinephrine	Inferior alveolar nerve block	70
Mason R et al. USA, 2009 [22]	prospective, randomised, double-blind study	• 2% lidocaine and 1:100 epinephrine	infiltrations (maxilla)	60	Anesthetic success and the onset of pulpal anesthesia were not significantly different between 2% lidocaine with either 1:100,000 or 1:50,000 epinephrine and 3% mepivacaine for the lateral incisor and first molar. Increasing the epinephrine concentration from 1:100,000 to 1:50,000 in a 2% lidocaine formulation significantly decreased pulpal anesthesia of short duration for the lateral incisor but not the first molar. For both the lateral incisor and first molar, 3% mepivacaine significantly increased pulpal anesthesia of short duration compared with 2% lidocaine with either 1:100,000 or 1:50,000 epinephrine.
		• 2% lidocaine and 1:50k epinephrine
		• 3% mepivacaine plain
Forloine A et al. USA, 2010 [23]	prospective, randomised, double-blind study	• 2% lidocaine and 1:100 epinephrine	Maxillary block	50	The high tuberosity approach to the maxillary second division nerve block with both anesthetic formulations resulted in a high success rate (92%–98%) for the first and second molars. Approximately 76%–78% of the second premolars were anesthetized with both anesthetic formulations. Both anesthetic formulations were ineffective for the anterior teeth and first premolars. The use of 3% mepivacaine provided a significantly shorter duration of pulpal anesthesia than 2% lidocaine with 1:100,000 epinephrine in the molars and premolars.
Forloine A et al. USA, 2010 [23]	prospective, randomised, double-blind study	• 3% mepivacaine plain	Maxillary block	50
Lawaty I et al. USA, 2010 [24]	prospective, randomised, double-blind study	• 2% mepivacaine and 1:20k levonordefrin	infiltration (maxilla)	60	Anesthetic success (obtaining 2 consecutive 80 readings with the electric pulp tester within 10 minutes ) was not significantly different between 2% mepivacaine with 1 : 20,000 levonordefrin and 2% lidocaine with 1 : 100,000 epinephrine for the central incisor and first molar. However, neither anesthetic agent provided an hour of pulpal anesthesia.
Lawaty I et al. USA, 2010 [24]	prospective, randomised, double-blind study	• 2% lidocaine and 1:100k epinephrine	infiltration (maxilla)	60
Berberich G et al. USA, 2009 [19]	prospective, randomised, double-blind study	• 2% lidocaine and 1:100k epinephrine	intraoral, infraorbital nerve block	40	The intraoral, infraorbital nerve block was ineffective in providing profound pulpal anesthesia of the maxillary central incisor, lateral incisor, and first molar. Successful pulpal anesthesia of the canine and first and second premolars ranged from 75%–92% by using 2% lidocaine with 1:100,000 and 1:50,000 epinephrine. However, pulpal anesthesia did not last for 60 minutes. The use of 3% mepivacaine provided a shorter duration of anesthesia than the lidocaine formulations with epinephrine in the canines and premolars.
		• 2% lidocaine and 1:50k epinephrine
		• 3% mepivacaine plain
Boonsiriseth K et al. Thailand, 2017 [57]	randomised single blind comparative split mouth design	• 4% lidocaine and 1:100k epinephrine	Inferior alveolar nerve block	22	The use of 4% articaine for the inferior alveolar nerve block was clinically more effective in the onset of subjective and objective anesthesiaas compared with the use of 4% lidocaine.
Boonsiriseth K et al. Thailand, 2017 [57]	randomised single blind comparative split mouth design	• 4% articaine and 1:100k epinephrine	Inferior alveolar nerve block	22