paraesthesia after local anaesthetics: an analysis of reports to the fda adverse event reporting...

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Article Type: Original Article

Paraesthesia after Local Anaesthetics: An Analysis of Reports to the FDA

Adverse Event Reporting System

Carlo Piccinni1*, Davide B. Gissi2*, Andrea Gabusi2, Lucio Montebugnoli2 and Elisabetta Poluzzi1

* contributed equally to the work

1. Department of Medical and Surgical Sciences - Pharmacology Unit, University of Bologna, Bologna,

Italy.

2. Department of Biomedical and Neuro-Muscular Sciences - Oral Sciences Unit, University of Bologna,

Bologna, Italy

Running Title: Paraesthesia after Local Anaesthetics

Author for correspondence: Elisabetta Poluzzi, University of Bologna, Department of Medical and Surgical

Sciences - Pharmacology Unit, Via Irnerio 48, 40126, Bologna (email: [email protected]).

Abstract: This study was aimed to evaluate the possible alert signals of paraesthesia by local anaesthetics,

focusing on those used in dentistry. A case/non-case study of spontaneous adverse events recorded in

FAERS (FDA Adverse Event Reporting System) between 2004 and 2011 was performed. Cases were

represented by the reports of reactions grouped under the term “Paraesthesias and dysaesthesias” involving

local anaesthetics (ATC:N01B*); non-cases were all other reports of the same drugs. Reporting odds ratios

(ROR) with the relevant 95% confidence intervals (95CI) were calculated. Alert signal was considered when:

number of cases >3 and lower limit of ROR 95CI >1. To estimate the specificity of signals for dentistry, the

analysis was restricted to the specific term "Paraesthesia Oral" and to reports concerning dental practice.

Overall, 528 reports of "Paraesthesias and dysaesthesias" were retrieved, corresponding to 573 drug reaction

This article is protected by copyright. All rights reserved.

pairs (247 lidocaine, 99 bupivacaine, 85 articaine, 30 prilocaine, 112 others). The signal was significant only

for articaine (ROR=18.38; 95CI=13.95-24.21) and prilocaine (2.66; 1.82-3.90). The analysis of the specific

term "Oral Paraesthesia" retrieved 82 reports corresponding to 90 drug reaction pairs (37 articaine, 19

lidocaine, 14 prilocaine, 7 bupivacaine, 13 others) and confirmed the signal for articaine (58.77; 37.82-

91.31) and prilocaine (8.73; 4.89-15.57). The analysis of reports concerning dental procedures retrieved a

signal for articaine, both for any procedures (8.84; 2.79-27.97) and for non-surgical ones (15.79; 1.87-

133.46). In conclusion, amongst local anaesthetics, only articaine and prilocaine generated a signal of

paraesthesia, especially when used in dentistry.

Local anaesthetics are the most used drugs in dentistry. They play a crucial role also in ophthalmology,

dermatology and different kinds of local surgery, due to their effectiveness in pain control and their safety

profile [1]. Adverse effects of local anaesthetics, especially in dentistry, are generally rare and, so far few

data on this issue are available [2].

One such potential complication of local anaesthetic administration is “paraesthesia”, defined as a

neuropathy with altered sensations and persistent anaesthesia [3-4] and no treatment is still available to solve

this condition. Symptoms related to paraesthesia may be manifold and include impaired sensory function

such as anaesthesia or hyperaesthesia, and neurosensory disturbances.

Concerning the oral paraesthesia, a possible additional symptom is the impairment of the gustatory function

due to the lingual nerve injury [5].

In dentistry, most oral paraesthesia are caused by direct trauma associated with a surgical procedure, such as

a dental extraction or orthognathic surgery. However, various authors have reported that paraesthesia can

also occur after local anaesthesia in non-surgical dentistry [6-9]. The mechanism underlying non-surgical

paraesthesia is not known. Different hypotheses have been suggested in order to explain the relationship

between local anaesthetics and subsequent paraesthesia: 1) direct trauma caused by the penetration of the

needle 2) haemorrhagic damage 3) nerve compression caused by the perineural oedema following the

injection 4) neurotoxicity of the local anaesthetics [3].


Neurotoxicity of local anaesthetics is a controversial topic [1, 10-11]: different studies have suggested that

local anaesthetic formulations may have the potential for neurotoxicity, in particular articaine 4% and

prilocaine 3–4% [6, 8-9, 12-17]. As a matter of fact, articaine is the most used local anaesthetic in many

countries [18], while prilocaine is scarcely used in clinical practice [19].

Evidence supporting the neurotoxicity of local anaesthetics emerged from the analysis of paraesthesia

persistency after injection. The severity of oral paraesthesia is related to the length of the altered sensations;

despite in the most of cases a nerve, affected abnormally by local anaesthetic, spontaneously recovers in an

8-week period [15], in some cases this adverse event could be prolonged and persist for 6-18 months or even

make the nerve unable to fully recover. In dental practice, paraesthesia was described for any local

anaesthetic. Van Eaden [16], Meechan [14] and Pedlar [17] reported a small number of patients where a

prolonged paraesthesia (more than 18 months) occurred after inferior dental block injection with articaine.

This risk was also investigated by observational studies [6, 9, 12] with debating results, but no formal

pharmacovigilance analyses were performed on this possible safety issue. Moreover, data on possible

differences within the therapeutic group of local anaesthetics are still conflicting. Therefore, this study was

aimed to investigate possible alert signals of paraesthesia by local anaesthetics, focusing on the specific oral

paraesthesia occurring in dentistry practice, through the statistical analysis of spontaneous adverse event

reports collected in the FDA Adverse Event Reporting System (FAERS).

Methods

Data were obtained from the FDA Adverse Event Reporting System (FAERS) system, containing all reports

of adverse drug events spontaneously reported by health care professionals, manufacturers and consumers

from the USA and serious and unlabeled spontaneous reports from non–U.S. countries [20]. In this database,

the adverse events are codified by Medical Dictionary for Regulatory Activities (MedDRA) terminology

[21], whereas drugs are reported as product name, therefore requiring a specific handling to be coded.

Moreover, the database contains various duplicate and multiple records that need to be identified and

removed before the analysis. We fully describe all these procedures elsewhere [22].


For the purpose of this study, we collected all adverse drug reactions (ADRs) reported with the use of any

local anaesthetic (searched by using the ATC code: N01B), in the period of 2004 to 2011, and we applied a

case-non case methodology [23]. Cases were represented by the reports of reactions included in the

MedDRA high-level term (HLT) “Paraesthesias and dysaesthesias” for a given local anaesthetic; non-cases

were all other reports of the same drug. To test the signals of paraesthesia by local anaesthetics, we

performed a disproportionality analysis by estimating the Reporting Odds Ratios (ROR), with corresponding

95% confidential interval (95% CI). This measure compares the proportion of the adverse event of interest

for a drug with the corresponding proportion for all other drugs [24]. Association was formally defined

when: number of cases was>3, ROR >1 and lower limit of 95%CI >1.

Since a report could contain more than one reaction and it could refer to more than one drug, analyses were

performed both by number of reports and by number of drug-reaction pairs.

To estimate the influence of this association in dentistry, two secondary analyses were performed; (i) by

using the specific Preferred Term (PT) "Paraesthesia Oral", belonging to the group of terms investigated in

the primary analysis; (ii) by selecting only reports concerning the use of local anaesthetics in dental practice

within the HLT “Paraesthesias and dysaesthesias”. For this last analysis, dental procedures were also

distinguished in “non-surgical”, “surgical” and “unspecified” procedures.

Stata/SE version 11.0 for Windows was used for statistical analysis.

Results

From 2004 to 2011 were collected 17,246 ADR reports for any local anaesthetic substance, resulting in

18,574 drug reaction pairs. Out of these, 528 reports of "Paraesthesias and dysaesthesias" related to local

anaesthetics were retrieved, corresponding to 573 drug reaction pairs. Among this group of terms, not

otherwise specified “paraesthesia” represented the 46.9% of all local anaesthetic-related reports, “burning

sensation” the 22.2%, “paraesthesia oral” the 13.9% and “hyperesthesia” the 5.58% (table 1).

The highest number of reports was found for lidocaine (247 reports), followed by bupivacaine (99), articaine

(85), combination of different local anaesthetics (45) and prilocaine (30). A significant disproportionality of

“Paraesthesias and dysaesthesias”, was found for articaine (ROR 18.38; 95% CI 13.95-24.21), and prilocaine


(2.66; 1.82-3.90, table 2). Other local anaesthetics did not show disproportionality signals according to the

defined thresholds.

The secondary analysis of the specific term "Paraesthesia Oral" retrieved 82 cases, corresponding to 90 drug

reaction pairs: 37 with articaine, 19 lidocaine, 14 prilocaine, 7 bupivacaine, 13 other local anaesthetics. This

analysis confirmed the disproportionality signals of the primary analysis, founding a statistical significant

ROR for articaine (58.77; 37.82-91.31) and prilocaine (8.73; 4.89-15.57, table 3). Mepivacaine showed a

weaker signal of "Paraesthesia Oral" (1.59; 0.88-2.86).

The secondary analysis of the reports concerning dental procedures collected 115 reports corresponding to

126 ADRs involving local anaesthetics specifically used in dental practice. Out of these, 23 cases of

“Paraesthesias and dysaesthesias” were found, 19 of them involving articaine. The ROR for articaine was

statistically significant both analysing any dental procedures (8.84; 2.79-27.97) and restricting the analysis to

non-surgical procedures (15.79; 1.87-133.46), whereas the statistical significance was missed for surgical

and unspecified procedures (table 4).

Discussion

This study underlined alert signal of paraesthesia for articaine and prilocaine, rather than other local

anaesthetics. This association was even stronger when the specific “oral paraesthesia” was considered and,

specifically for articaine, when non-surgical dental procedures were investigated.

Our results are consistent with other studies from Canada, Denmark and USA suggesting that the use of

prilocaine [15, 25], articaine [9] or both drugs [6, 12-13] may be associated with an increased risk of

paraesthesia. However, our study provided the contribution coming from the analysis of the largest

spontaneous reporting database, by using a standard pharmacovigilance methodology, in the investigation of

this safety issue.

A weaker signal demonstrated by mepivacaine only for oral paraesthesia should not be ignored, although the

number of cases (only 4) is barely compliant with signal criteria.

The exact mechanism underlying paraesthesia related to articaine or prilocaine still remains unknown.


Nerve injury was reported especially after mandibular block analgesia, and lingual nerve was affected in 64-

79% of all reported cases [6, 9, 12-13]. A direct trauma is a first possible explanation about association

between paraesthesia and local anaesthesia.

When mandibular block analgesia was performed, the patient’s mouth is wide open; this could stretch the

lingual nerve and deflect the needle used for the anaesthetic administration. Therefore, the needle can

penetrate the nerve sheath and consequently could cause (1) direct damage of nerve fibres; or (2) damage of

small blood vessels located within the nerve, leading to intraneural haemorrhage; or (3) damage of

connective tissues within the nerve, producing oedema within the nerve sheath. All 3 events can lead to

paraesthesia, in a transient or permanent way [10, 15]. However, this phenomenon does not completely

explain the association between oral paraesthesia and local anaesthetic administration, especially articaine

and prilocaine. Indeed, a toxic effect of local anaesthetics may be related with increased risk of paraesthesia.

Notably, articaine and prilocaine are available in dental cartridges as solutions in oncentrations of 3-4%

(articaine 4%, prilocaine 3-4%). These concentrations are the highest among injectable local anaesthetics

marketed for dentistry practice (e.g. lidocaine used in dentistry is concentrated 2%). The local anaesthetic

concentration seems to play an important role for nerve injury: Cornelius et al. found the extinction of

sensory-evoked potentials in 90% of rats treated with microinjection of articaine 4% in sciatic nerve,

whereas only in 10% of the rats treated with articaine 2% or xylocaine 2% [26]. Moreover, by performing a

histopathological analysis, this work found a tissue damage with articaine 4% and not with articaine 2% [26].

This mechanism could explain the high rate of oral paraesthesia. Around the area of mandibular block

injection, the lingual nerve typically has fewer fascicles than the inferior alveolar nerve and may be

unifascicular in about a third of patients [[27]. Therefore, the frequent occurrence of lingual nerve

paraesthesia may be related to its fascicular pattern.

Our study represents a formal pharmacovigilance analysis conducted by using the biggest publicly available

archive of drug-related adverse event reports. It compared all local anaesthetics used in clinical practice and

all kinds of paraesthesia reported worldwide.

As for all studies of spontaneous adverse events, also for our analysis the following limitations should be

acknowledged [28]: under-reporting and over-reporting phenomena, notoriety bias (increased reporting

following media attention and publicity resulting from advertising or regulatory actions on a safety issue),


Weber effect (peak of reports especially in the first drug-marketing period) missing or misspelled data.

Additional weaknesses of our study were represented by the lack of data on some patient habits and

conditions (e.g., smoking or comorbidity), clinical procedure (e.g. orthognatic surgery, mandibular block

analgesia) and length of adverse event (this last aspect could provide information on severity of

paraesthesia).

Nevertheless these weaknesses, the safety disproportionality signals emerged from our study should

stimulate more specific researches to confirm or reject the causality relationship between the anaesthetic

solutions containing articaine or prilocaine and paraesthesia, and to quantify the magnitude of the hazard.

However, due to the unavailability of worldwide sales data of local anaesthetics, our analysis was not able to

estimate the reporting rate of paraesthesia for each active substance.

In the light of our findings, clinicians, especially dentists, should consider risks and complications of

articaine or prilocaine and the concentrations of the drug in the choice of local anaesthetic for their patients.

Moreover, they should pay attention to any symptoms suggesting a possible paraesthesia after anaesthetic

administration, and they should report this adverse event to their pharmacovigilance service.

Acknowledgements

The authors thank Ariola Koci (statistician of Department of Medical and Surgical Sciences - Pharmacology

Unit, University of Bologna) for her support in data management and data extraction.

Founding Source

This research was supported by funds from the University of Bologna (RFO 2012).

Conflict of Interest

All authors declare no conflict of interests.


Prior presentations

A part of the results was presented as a poster at the 13thISoP (International Society of Pharmacovigilance)

Annual Meeting in Pisa, Italy, 1-4 October 2013.

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Tables

Table 1.Reports and Drug Reaction Pairs involving local anaesthetics grouped by MedDRA (Medical Dictionary for Regulatory Activities) hierarchy

MedDRA Hierarchy Reports Drug-Reaction Pairsa

N (%) N (%)

HLT: High Level Term

Paraesthesias and dysaesthesias 528 573

PTs: Preferred Termsb Paraesthesia 277 (46.9) 301 (47.3)

Burning sensation 131 (22.9) 138 (21.6)

Paraesthesia oral 82 (13.9) 90 (14.1)

Hyperaesthesia 33 (5.6) 37 (5.8)

Dysaesthesia 22 (3.7) 25 (3.9)

Skin burning sensation 21 (3.5) 22 (3.4)

Formication 17 (2.9) 18 (2.8)

Oral dysaesthesia 3 (0.5) 3 (0.5)

Injection site paraesthesia 1 (0.2) 1 (0.2)

Injection site anaesthesia 1 (0.2) 1 (0.2)

Burning mouth syndrome 1 (0.2) 1 (0.2)

Burning feet syndrome 1 (0.2) 1 (0.2)

Application site anaesthesia 1 (0.2) 2 (0.3)

Total 591 (100.0) 640 (100.0)a.Drug reaction pairs could be larger than Reports since a single report can be related to more than one drug. b.Reports grouped by PT could be more than Reports grouped by HLT since a single report can contain more than one PT belonging to the same HLT The following PTs, belonging to HLT “Paraesthesias and dysaesthesias”, were not indicated in any reports involving local anaesthetics: Burning sensation mucosal, Fabry's disease, paraesthesia mucosal, Lhermitte's sign, intranasal paraesthesia, Tinel's sign, paraesthesia of genital male, paraesthesia of genital female, dysaesthesia pharynx, implant site paraesthesia, hand-arm vibration syndrome, acrotrophodynia, infusion site paraesthesia, infusion site anaesthesia, vessel puncture site anaesthesia, vessel puncture site paraesthesia, injection site dysaesthesia, vaccination site paraesthesia, application site hyperaesthesia, application site paraesthesia.


Table 2. ROR of “Paraesthesias and dysaesthesias” for local anaesthetics

Active substance Casesa All

ADRs ROR 95% CI

Lidocaine 247 7,720 1.07 0.90-1.26

Bupivacaine 99 2,843 1.16 0.93-1.45

Articaine 85 254 18.38 13.95-24.21 Combinations of local anaesthetics 45 2,687 0.50 0.36-0.67

Prilocaine 30 396 2.66 1.82-3.90 Ropivacaine 19 845 0.71 0.45-1.13

Mepivacaine 12 251 1.59 0.88-2.86

Cocaine 9 2,441 0.10 0.05-0.20

Capsaicin 7 173 1.33 0.62-2.84

Benzocaine 5 214 0.75 0.31-1.83

Phenol 5 185 0.87 0.36-2.13

Levobupivacaine 3 91 1.07 0.34-3.40

Tetracaine 3 120 0.80 0.25-2.54

Procaine 2 181 0.35 0.09-1.41

Dyclonine 1 6 6.29 0.73-53.95

Ethyl chloride 1 15 2.25 0.29-17.11

Other local anaesthetics 0 152 n.a. n.a.

Total 573 18,574 a. Cases of “Paraesthesias and dysaesthesias”. Statistical disproportionality signals in bold. ADR: Adverse Drug Reaction; ROR: Reporting Odds Ratio; 95% CI: 95% Confidence Interval; n.a.: not available

Table 3. ROR of “Paraesthesia Oral” for local anaesthetics

Active substance Casesa All

ADRs ROR 95% CI

Articaine 37 254 58.77 37.82-91.31 Lidocaine 19 7,720 0.37 0.23-0.62

Prilocaine 14 396 8.73 4.89-15.57 Bupivacaine 7 2,843 0.47 0.21-1.01

Mepivacaine 4 251 3.43 1.25-9.43 Combinations of local anaesthetics 3 2,687 0.20 0.06-0.64

Benzocaine 2 214 1.96 0.48-8.01

Cocaine 2 2,441 0.15 0.04-0.61

Phenol 1 185 1.12 0.15-8.06

Tetracaine 1 120 1.73 0.24-12.55

Other local anaesthetics 0 1,463 n.a n.a.

Total 90 18,574 a.Cases of “Paraesthesia Oral”. Statistical disproportionality signals in bold. ADR: Adverse Drug Reaction; ROR: Reporting Odds Ratio; 95% CI: 95% Confidence Interval; n.a.: not available


Table 4. ROR of “Paraesthesias and dysaesthesias” for local anaesthetics used in dental practices, grouped in

surgical, non-surgical and unspecified procedures

Any dental procedures

Non-surgical dental proceduresb

Surgical dental proceduresc

Unspecified dental proceduresd

Active substance

Casesa

All ADRs

ROR

95% CI

Casesa

ROR

95% CI Casesa

ROR

95% CI Casesa

ROR

95% CI

Articaine 19 55 8.84

2.79-27.97

10 15.79

1.87-133.46

3 9.43

0.84-105.79

6 4.50

0.75-26.93

Prilocaine 1 6 0.89

0.1-8.01

1 2.35

0.19-28.5

0 n.a.

n.a 0 n.a.

n.a

Lidocaine 1 30 0.12

0.01-0.9

0 n.a. n.a 0 n.a.

n.a 1 0.57

0.06-5.78

Bupivacaine 1 5 1.13

0.12-10.56

0 n.a. n.a 0 n.a.

n.a 1 3.43

0.19-62.12

Procaine 1 8 0.62

0.07-5.33

0 n.a. n.a 1 n.a.

n.a 0 n.a.

n.a

Other local anaesthetics

0 22 n.a. n.a 0 n.a. n.a 0 n.a.

n.a 0 n.a.

n.a

Total 23 126 11 4 8 a. Cases of “Paraesthesias and dysaesthesias” b Non-surgical dental procedures were: artificial crown procedure; dental care; dental cleaning; dental cosmetic procedure; dental prosthesis placement; endodontic procedure. c Surgical dental procedures were: dental implantation; tooth abscess; tooth extraction; tooth infection; wisdom teeth removal. d. Unspecified dental procedures were: dental operation; oral infection; teething; tooth disorder. Statistical disproportionality signals in bold. ADR: Adverse Drug Reaction; ROR: Reporting Odds Ratio; 95% CI: 95% Confidence Interval; n.a.: not available

paraesthesia after local anaesthetics: an analysis of reports to the fda adverse event reporting...

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