International Dental Journal 2020; 70: 79–84

CONCISE CLINICAL REVIEW

doi: 10.1111/idj.12540

Adverse drug reactions in dentistry

Aviv Ouanounou1, Kester Ng2 and Peter Chaban2
1
Department of Clinical Sciences, Pharmacology & Preventive Dentistry, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada;
2
Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.

An adverse drug reaction (ADR) is an undesirable effect of a drug. ADRs are possible with any medication that is pre-
scribed or administered in the dental office. While most pharmacological agents in use today have favourable drug pro-
files and are relatively safe, the prudent clinician must be aware of the potential ADRs that can occur and be prepared
to manage any complications. Here we review the most commonly used agents in dentistry, namely local anaesthetics,
sedatives, analgesics and antibiotics, and their ADRs and management.

Key words: Adverse reactions, drug interactions, dental pharmacology, analgesics, antibiotics

room. A referral should be made to the patient’s fam-

INTRODUCTION
An adverse drug reaction (ADR) can be defined as
any undesirable effect of a drug1,2. It is important to
distinguish between an ADR and an allergy: an allergy
refers to an immune-mediated response to a medica-
tion, for example anaphylaxis, whereas an ADR can
be any effect that is not therapeutically desired, for
example sedation. In essence, an allergy can be an
ADR but not all ADRs are allergies3.
True drug allergies can be identified by the presen-
tation of any definite immunological mechanism (T-
cell or drug-specific antibody). Such reactions occur
immediately or after a delay, and may be life-threat-
ening to the patient. Immediate drug allergies com-
monly present as urticaria, rhinitis, angioedema,
bronchospasm, conjunctivitis, gastrointestinal (GI)
upset or anaphylaxis (which has the potential to cause
cardiovascular collapse)4,5. Delayed drug allergies
commonly present on the skin with possible symp-
toms, including delayed urticaria, maculopapular
eruptions, vasculitis and blistering diseases6. If a prac-
titioner is concerned about a patient having an allergic
drug reaction, they should immediately stop adminis-
tration of the suspected drug, treat the reaction, docu-
ment the drugs taken (dose, type, duration), and
record any signs and symptoms7,8. In severe cases,
emergency medical services should be summoned and
the patient accompanied to the nearest emergency
© 2020 FDI World Dental Federation
ily physician to investigate the allergy further.
In modern dental practice only a few categories of
pharmacological agents are ubiquitously used; these
include local anaesthetics (LA), central nervous system
depressants (e.g. nitrous oxide, benzodiazepines and
general anaesthetics), analgesics [e.g. non-steroidal
anti-inflammatory drugs (NSAIDs), acetaminophen
and opioids] and antibiotics (e.g. penicillin, clin-
damycin and metronidazole). It is critical that the
dental healthcare team is well equipped to manage
any foreseeable and unforeseeable ADRs that occur in
the dental office setting. In addition, it is the responsi-
bility of the healthcare professional to thoroughly
understand the health status of their patients when-
ever prescribing new drugs or altering dosages to
avoid provoking avoidable ADRs in their patients.
LOCAL ANAESTHETICS AND THEIR
VASOCONSTRICTORS
Local anaesthetics are the most commonly used
drugs in dental practice9. It is estimated that each
Canadian dentist will administer close to 1,800 car-
tridges per year; in the USA alone, over 300 million
cartridges are administered per year10. LA are gener-
ally considered to be safe10; however, the healthcare
practitioner must take responsibility to ensure that
the dosage and concentration is tailored towards
79
Ouanounou et al.

each patient to avoid potential ADRs, both local and
systemic.
Local complications associated with LA administra-
tion include tissue necrosis and direct neurotoxicity.
Tissue necrosis occurs due to disruption of the vascu-
lature-supplied tissue, and is related to the irritating
nature of the solution, large volumes being adminis-
tered, or constriction of the vasculature by vasocon-
strictors in the LA cartridge (e.g. epinephrine or
levonordefrin). Management of these conditions is lar-
gely symptomatic in nature and avoidance is most
prudent. Careful administration of LA, particularly in
areas of tightly-bound tissue such as in the palate, will
reduce the likelihood of ischaemia.
Direct neurotoxicity to nerve trunks resulting in
paresthesia has been reported in the literature to occur
at higher frequency with anaesthetic solutions of higher
concentration such as 4% articaine and prilocaine when
administered as blocks (see Haas and Lennon10 and
Garisto et al.11). Others suggested that this may not be
the case when using articaine12–14. The clinician must
carefully consider whether the benefits of a 4% solution
outweigh the potential for complications. Management
of paresthesia entails monitoring and potential referral
to an oral surgeon with experience and background in
the management of these conditions. Fortunately most
cases of paresthesia are transient and resolve within
8 weeks; however, in some cases neurological deficits
may be permanent10. Other complications associated
with LA are a combination of ADR and technique, such
as intramuscular injection resulting in trismus.
As LA is removed in the cardiovascular system
(CVS) and may be administered directly into the CVS
due to poor technique, systemic complications can
occur. All LAs are central nervous system depressants,
and can result in drowsiness, seizures and even coma
at high enough blood levels in cerebral circulation10.
While unlikely to occur in an adult patient save for
extreme administration of LA, this is much more of a
concern in paediatric patients who have much lower
body weight10. Clinicians should be aware of calcula-
tions of maximum dosages for LA (Table 1). Another
possible systemic ADR is methemoglobinemia, an
uncommon reaction most often associated with prilo-
caine, and topical benzocaine. Methemoglobinemia
results in cyanosis that does not respond to 100%
oxygen, and can result in nausea, sedation, seizures,
and coma at high levels. For patients with congenital
methemoglobinemia, those mentioned anaesthetics
should be avoided10.
Today, the most common vasoconstrictor in LA
formulations is epinephrine, and is available in
1:50,000, 1:100,000 and 1:200,000 formulations. Epi-
nephrine is a potent cardiovascular agent, and at high
doses can result in increased heart rate, blood pres-
sure, and potential cardiovascular emergency. The
clinician must be cautious with regards to how much
is administered.
SEDATIVES AND GENERAL ANAESTHETICS
All sedatives and general anaesthetic agents are cap-
able of causing respiratory depression in a dose-de-
pendent manner, with the intensity of depression
increased more readily when multiple sedatives are
administered. It is important to distinguish a physio-
logical depression of respiration from an anatomical
one – i.e. one that is caused due to loss of muscle
tone. Loss of muscle tone in the glossopharyngeal
musculature reduces pharyngeal patency, as does mal-
positioning of the tongue. Such anatomical obstruc-
tion can occur at any level of sedation, and can be
managed with airway techniques such as a head tilt,
chin lift or an oropharyngeal airway.
Physiological depression relates to alterations to the
mechanisms related to respiration. Respiration is
dependent upon both a central hypercapnic drive and
a peripheral hypoxemic drive with the sedative classes
impacting these drives differently. As dosages increase,
the differences become increasingly minimal, and both
central and peripheral drives are affected. With
regards to tidal volume and respiratory rate, in gen-
eral, the inhalation anaesthetics (e.g. sevoflurane)
depress tidal volume while increasing the respiratory
rate, while intravenous agents and opioids depress
both. Benzodiazepines tend to depress respiration the

Table 1 Canadian maximum recommended dosages (MRD)* of LA and sample calculation for determining maxi-
mum amount of LA that can be safely administered. Modified from Haas and Lennon10
Anaesthetic Maximum Sample calculation

Lidocaine (e.g. Xylocaine)
Articaine (e.g. Astracaine)
Bupivacaine (e.g. Vivacaine)
Mepivacaine (e.g. Scandonest)
Prilocaine (e.g. Citanest)
7 mg/kg up to 500 mg
7 mg/kg up to 500 mg
2 mg/kg up to 200 mg
6.6 mg/kg up to 400 mg
8 mg/kg up to 500 mg
Patient weighs 20 kg (44 lb), dentist administers lidocaine 2%
Maximum = 7 mg/kg 9 20 kg = 140 mg
Lidocaine 2% = 20 mg/mL of drug
Max amount = 140 mg/ 20 mg/mL = 7 mL
Max cartridge = 7 mL/ 1.8 mL/ cartridge = 3.9 cartridges
Therefore, the dentist can administer up to 3.9 cartridges of lidocaine 2%.

*Values in Table 1 represent Canadian MRDs and therefore may vary significantly from country to country. It is recommended that each clini-
cian investigate the manufacturer’s recommendations.

80 © 2020 FDI World Dental Federation

 Adverse drug reactions in dentistry

Table 2 Impacts of common sedatives and general
anaesthetics on heart rate, arterial pressure and venti-
lation. Modified from Butterworth et al.29
Agent Heart rate Arterial pressure
Diazepam =+*
Midazolam +*
Propofol =
Ketamine ++ ++
Fentanyl = elimination after sulphation or glucuronidation (Fig-
Nitrous oxide = =
Desflurane =+
Sevoflurane = by glutathione and is also eliminated. However, in the
‘*’ Increase due to reflex response to decreased arterial pressure. ‘+’
indicates an increase. ‘ ’ indicates a decrease. ‘=’ indicates no
change.
least. Outside of respiratory effects, sedatives and gen-
eral anaesthetics also have impacts on the CVS and
may result in changes to heart rate and arterial blood
pressure. Finally, the benzodiazepines and propofol
result in anterograde amnesia, which may be of con-
cern where instructions need to be given to the patient
or where changes in treatment plan may occur during
the procedure (Table 2).
It is also worth reviewing the sedation continuum.
At minimal sedation (‘anxiolysis’), patients respond
normally to verbal stimulation. At moderate sedation
(‘conscious sedation’), purposeful response is made to
verbal or tactile stimulation. Deep sedation involves
purposeful response to repeated or painful stimulus.
At general anaesthesia, a patient does not respond to
pain. A purposeful response is not to be considered
withdrawal from a painful stimulus. See Table 3 for a
more detailed examination and summary of the con-
tinuum.
ANALGESICS
While numerous analgesics are available, here we
focus on the most commonly employed analgesics in
practice: acetaminophen, the NSAIDs, and opioids.
Acetaminophen
Acetaminophen is one of the safest analgesics avail-
able with almost no adverse effects when administered
to healthy individuals at conventional doses.10 The
most significant ADR associated with acetaminophen
is hepatotoxicity. Hepatotoxicity occurs due to the
accumulation of N-acetyl-p-benzoquinone imine
Ventilation
(NAPQI), a potentially toxic metabolite of acetamino-
phen15,16. This metabolite is formed from approxi-
mately 5% 15% of total acetaminophen intake, with
= the remaining 85% 95% undergoing immediate renal
=
ure 1). For healthy individuals NAPQI is conjugated
presence of excessive acetaminophen dosages, or in
individuals with compromised hepatofunction, hepa-
totoxicity becomes a grave concern.
The commonly accepted maximum dosage of aceta-
minophen in a healthy individual is 4 g per day; how-
ever, recent suggestions have been made to reduce this
dosage to 3 g per day17. Hepatotoxicity may occur if
a large bolus is taken at 7.5–10 g for adults (150 mg/
kg in children), with fatalities potentially occurring at
20 25 g. Because the dosage that induces hepatotoxi-
city is approximately double that of the daily maxi-
mum, the likelihood of adverse reactions is low
assuming proper drug instructions are given. In an
emergency overdose situation, individuals should be
treated with high-dose acetylcysteine to restore glu-
tathione enzyme reserves.
Non-steroidal anti-inflammatory drugs
While generally well tolerated, the most common
ADR associated with the NSAIDs relates to GI com-
plications, with the most widely feared relating to GI
bleeding and toxicity. GI toxicity is not considered
uncommon, with over 16,500 deaths in the USA
attributed to NSAIDs18. GI bleeding arises due to the
mechanism of action of NSAIDs, which inhibit prosta-
glandin synthesis, thereby diminishing the protective
effect prostaglandins have on mucosa. The prudent
clinician should therefore avoid prescribing NSAIDs
to any patient with a history of gastric ulcers or
bleeding, and should consider acetaminophen as the
drug of choice.
More rare is the possibility of triggering an anaphy-
lactoid reaction with NSAIDs. Bronchospasm and

Table 3 The sedation continuum

Minimal sedation Moderate sedation Deep sedation General anaesthesia

Responsiveness Either verbal Verbal and/or tactile To painful repeated stimulus No response even to pain
or tactile in combination
Airway Maintained Usually maintained Intervention may be needed Intervention usually needed
Ventilation Unaffected Adequate May require supplementation Frequently requires supplementation
Cardiovascular function Unaffected Usually maintained Usually maintained May be impaired
Protective reflexes Intact Intact Partial loss Absent

Modified from Ref. 30.

© 2020 FDI World Dental Federation 81

Ouanounou et al.
other signs and symptoms of allergy can occur in sus-
ceptible patients due to the leukotriene pathway of
action19. For patients suffering from severe asthma,
the clinician should avoid administration of NSAIDs,
as well as acetylsalicylic acid. Other potential ADRs
include impairment of renal function; however, these
typically require long-term, chronic administration of
NSAIDs.
Opioids
All opioids produce dose-dependent respiratory
depression, sedation and GI upset, including constipa-
tion, nausea and vomiting17. Mood alterations are
also possible, and may appear as euphoria or dyspho-
ria (if unpleasant). Unfortunately, opioid misuse and
addiction is rising at a devastating rate throughout
Canada and the USA, to the point where it is now
considered an ‘opioid crisis’20. Patients suffering from
opioid use disorder often require long-term sustained
Figure 1. Main pathway of acetaminophen metabolism.
Table 4 Post-operative pain management protocol in dentistry
Anticipated post-operative Initial 24 hours
pain
Mild to moderate 400–600 mg ibuprofen q6h
Moderate to severe 400–600 mg ibuprofen
+500 mg acetaminophen q6h
Severe 400–600 mg ibuprofen
+650 mg acetaminophen
+10 mg hydrocodone q6h for 24–48 hours
‘q’ = every, ‘h’ = hours.
From Ref.31.
82
treatment, most commonly methadone, in order to
maintain recovery. As prescribers of approximately
12% of all opioids in North America, dentists must
make efforts to avoid opioid prescriptions unless
absolutely necessary21. See Table 4 for recommended
post-surgical pain management protocol. Opioid pre-
scriptions should be written judiciously after an exten-
sive review of the patient’s health history to minimise
the patient’s risk for developing physical dependence,
a devastating opioid adverse drug effect.
ANTIBIOTICS
Excluding anaphylactic reactions, the most commonly
used antibiotics in dentistry today are tolerated well.
The most common ADR for all antibiotics involves
GI upset (e.g. diarrhoea, nausea, vomiting). Approxi-
mately 2%–10% of all antibiotics used will result in
diarrhoea, reaching upwards of 25% in the case of
Augmentinâ (amoxicillin and clavulanic acid)22. Of
After 24 hours
400 mg ibuprofen q4–6h
400 mg ibuprofen
+500 mg acetaminophen q6h
400–600 mg ibuprofen
+500 mg acetaminophen q6h
© 2020 FDI World Dental Federation

Table 5 Protocol for the management of Clostridium
difficile infection
Stop all antibiotics
Keep the patient hydrated
Refer to a physician
Prescribe:
Vancomycin 500 mg po qid for 2 days (if severe)
Vancomycin 125 mg po qid for 10–14 days
Metronidazole 500 mg po tid for 7–14 days
Table 6 Preventive protocol for Clostridium difficile
infection
Only prescribe antibiotics when absolutely necessary
Wash hands with soap and warm water between each patient
Use disposable gloves and gowns when in the same room as
infected patients
Thorough disinfection of room/chair with chlorine bleach
between patients
greater concern is the potential for development of
more serious opportunistic infections like Clostridium
difficile or yeast infections following administration of
antibiotics. The former is most commonly associated
with the usage of clindamycin, though any antibiotic
may potentially result in C. difficile infection. The
protocol for the management of C. difficile infection
is outlined in Table 5. If a patient suspects they may
have a C. difficile infection, they should immediately
contact their family physician to be evaluated. In
cases where a patient does not have a family physician
or is displaying severe symptoms, such as bloody diar-
rhoea or urine, they should go to their nearest hospi-
tal emergency room. The prevention protocol is
outlined in Table 6. Fungal infections are generally
managed through prescription of a topical antifungal
such as nystatin.
It is also extremely important to educate patients
on their restrictions when taking specific antibiotics to
avoid the potential for ADRs. Users prescribed
metronidazole, an antibiotic effective at treating
anaerobic bacterial infections, should be advised to
avoid alcohol intake due to metronidazole’s ability to
inhibit enzymes in the ethanol degradation path-
way24,25. Users may experience flushing, headaches,
nausea and cardiac palpitations26. Metronidazole
users should avoid alcohol intake for at least 3 days
after completing the full antibiotic course.
Another, more life-threatening, adverse drug inter-
action is that of clarithromycin, erythromycin and azi-
thromycin with digoxin25. These antibiotics inhibit
the elimination of digoxin from the bloodstream and
thus have the potential to severely elevate digoxin
blood levels, causing digitalis toxicity27,28. Signs of
digitalis toxicity commonly include nausea, vomiting
© 2020 FDI World Dental Federation
Adverse drug reactions in dentistry
and irregular heartbeat. Less common symptoms may
include experiences of confusion, blurry vision, blind
spots and bodily oedema.
CONCLUSION
By and large, the pharmacological armamentarium for
the practicing dentist today is relatively safe. However,
the prudent clinician must be aware of potential ADRs
that can arise from drug administration and be comfor-
table with the management of such complications.
Acknowledgements
None.
Conflict of interest
None.
Funding information
No fundings was received for this review.
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Correspondence to:
Dr. Aviv Ouanounou,
Department of Clinical Sciences, Pharmacology &
Preventive Dentistry,
Faculty of Dentistry,
University of Toronto,
124 Edward Street Room 370,
Toronto, ON M5G 1G6, Canada.
Email: aviv.ouanounou@dentistry.utoronto.ca
© 2020 FDI World Dental Federation