A systematic review about analgesics used in dental implant surgery.

Analgesics effectively improved post-surgical outcomes like pain, patient satisfaction, and rescue medication requirements compared to placebo following dental implants. 

The use of dental implants has gradually elevated in the past few years. The oral rehabilitation of multiple or single edentulism with dental implants (a revolution in dentistry) is commonly used, and its use has increased in the current years. While intrasurgical pain can be effectively alleviated with anaesthetic agents, post-surgery pain remains a possible adverse effect of dental surgery.

Following dental implant placement surgery, people may present different degrees of post-surgery discomfort. The common adverse effects of surgical trauma are swelling and pain, resulting due to the release of inflammatory mediators. It is further influenced by several intervention-related factors (like the type of surgery, extension, and duration) and patient characteristics (like anxiety, stress level, heart rate, and blood pressure). Pain is usually moderate or mild. However, some people may witness severe pain.  Thus, post-surgery management has received the attention of several investigators.

Different classes of the drug-like benzodiazepine (midazolam), corticosteroids (betamethasone and dexamethasone), local anaesthetics (liposomal bupivacaine), NSAID (dexketoprofen trometamol, ibuprofen, lornoxicam, piroxicam, meloxicam, teloxicam, diclofenac diethylamine, and ketorolac), alpha-2 adrenergic receptor agonists (dexmedetomidine), and opioids (fentanyl and codeine) had been used for management of post surgical pain.

RATIONALE BEHIND RESEARCH

Numerous drugs and various protocols have been examined to manage post-surgery pain, but the effectiveness and treatment-associated adverse events are not clear yet. Therefore, this study was carried out.

OBJECTIVE

This study was conducted to summarize the available evidence on analgesic agents to alleviate post-surgery pain following dental implant placement and identify the best therapeutic protocols and knowledge gaps.

Literature search

Databases like Clinicaltrials.gov., MEDLINE/PubMed, Cochrane Central Register of Controlled Trials, SCOPUS, and EMBASE were comprehensively explored from data inception until June 2019 to find out the relevant studies. The search strategy carried out was devoid of any language restrictions. Furthermore, to discover studies of interest, the references of the accessed articles were also hand-searched.

Inclusion criteria

Studies were included in this systematic review if:

• they were parallel and crossover randomized controlled trials
• they included adult patients (aged 16 or more) undergoing multiple or single dental implant surgeries.
• they included the postoperative use of analgesic drugs (intervention)
• they included postoperative use of any analgesic drugs or placebo (comparator)
• they included outcomes such as patient satisfaction, the intensity of post-surgery pain, side effects, swelling, and rescue medication requirements.

Exclusion criteria

• The studies with no human subjects were eliminated.

Study selection and Data extraction

This study was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two researchers independently assessed search results, and screening of the abstracts and titles was also done. Full texts of eligible articles were procured.

From the incorporated articles, the critical data were independently extracted by two investigators. The evaluation of the inter-rater agreement was done using Cohen's kappa statistics. The outcomes measures, type of intervention, and study features (like country, trial design, publication year, age, and the number of recruited people) were extracted for each article. A third researcher reviewed the extracted data.

Risk of Bias and Quality assessment

To determine the risk of bias in randomized trials, two researchers appraised the bias risk of the incorporated studies using the Cochrane revised tool.

Five specific domains associated with the risk of bias of RCTs were determined:

1. Bias resulting from randomization process,
2. Bias due to deviations from the intended interventions,
3. Bias due to the missing outcome data,
4. Bias in the outcome measurement,
5. Bias in the selection of the reported results.

For each of the domains, a study could be at low or high bias risk. A third person was employed to reduce any inconsistencies in the study.

A narrative synthesis of incorporated studies was carried out since some aspects restricted the feasibility of a significant meta-analysis. To enhance clarity and readability for readers, the results from each study were summarized in tables utilizing a narrative approach rather than a quantitative approach.

Study outcomes

Decline in post-surgery pain after dental implant placement was the primary outcome.

Outcomes

Study and participant characteristics:

• A total of 10 parallel RCTs and one crossover RCT were included in the systematic review.
• The number of recruited subjects ranged from 20 to 117.
• The administration timing varied from 24 hrs prior to surgery to 72 hours after surgery.
• The type of analgesic drugs incorporated liposomal bupivacaine, dexamethasone,  dexketoprofen trometamol, ketorolac, caffeine, ketorolac + betamethasone, codeine, diclofenac diethylamine, midazolam + fentanyl, diclofenac sodium, dexmedetomidine + fentanyl, piroxicam, lornoxicam, meloxicam, ibuprofen, and teloxicam.

Study quality:

• Notably, four studies were at the low bias risk for all domains and were judged to be at low overall risk of bias.
• Five studies aroused few concerns due to the bias risk arising from the randomization process (vague info about concealing allocation sequence and presence of baseline imbalances).
• One study was at elevated risk of bias emerging from the randomization process (no concealment of the allocation sequence) and was considered at high overall risk-of-bias.
• One study was at greater risk of bias arising from the randomization process and considerable deviations from the intended interventions and was judged to be at greater risk of bias.

Effect of intervention on the outcome:

• Analgesic use was related to improved post-surgery outcomes (pain, participant's satisfaction, and rescue medication requirement) compared to placebo.

The findings of this study revealed that the use of analgesics in dental implant placement might be related to improved post-surgery outcomes. However, indications about the best analgesics could not be yielded. Unluckily, heterogeneity in the different timing of evaluation yields an inconclusive picture of these therapeutics' safety and efficacy. Nevertheless, various analgesics (lornoxicam, ibuprofen, dexamethasone, piroxicam, and dexketoprofen trometamol) displayed superiority in mitigating post-surgery pain with placebo. Furthermore, liposomal bupivacaine illustrated an improved pain-relieving effect when linked with an opioid-sparing post-surgery pain alleviation protocol.

The outcomes were consistent with the literature on post-surgery pain improvement following the third molar extraction operation, an extensively utilized pain model in dentistry. Investigation of different analgesics usually failed to recommend the best option to alleviate post-surgery pain. In a study by Samiera et al., codeine demonstrated superiority to caffeine in post-surgery pain relief. However, caffeine was found to be more effective than codeine in alleviating post-surgery swelling.

In another study by Li et al., dexmedetomidine was better in reducing post-surgery pain when compared to midazolam (both in association with fentanyl). NSAIDs exhibit a well-known mitigating effect on pain. As per the literature, controversial findings exist regarding the influence of NSAIDs on bone regeneration around implants. The results of an assessment by Gomes et al. indicated no deterioration in osseointegration with COX-1 inhibitors (both in long and short-term administration). However, their safe usage during the post-surgery period has not been illustrated.

Following oral surgery, corticosteroids are usually given to minimize the inflammatory response. While their efficacy in diminishing trismus and swelling after third molar extraction is well-accepted, there have been controversial results on their direct analgesic effect. Therefore, further investigation on different molecules at different dosages requires to be carried out to provide more insight on this aspect.

In this study, 4 mg of dexamethasone one hour before surgery plus 4 mg six hours after surgery led to more significant pain decline compared to placebo, with no vital difference compared to 600 mg ibuprofen given at the same time. Contrarily, betamethasone 3 mg given with ketorolac did not considerably lower post-implant pain. Glucocorticosteroids given for systemic diseases appear to have no effect on the osseointegration and survival of dental implants placed without bone grafting. Though opioids (like fentanyl and codeine) have well-known pain-relieving effects, other aspects (dependency, side effects, and abuse) should be considered when given for postoperative pain. Therefore, they should be given only for a short time and when an alternate therapeutic agent is not adequate.

Liposomal bupivacaine, a local anaesthetic formulation, is used to provide sustained-release analgesia. It consists of bupivacaine hydrochloride encapsulated within the multiple nonconcentric lipid bilayers. Hamilton et al. noted that its infiltration at the surgery site might minimize post-surgery pain compared to placebo. However, it could not show superiority to bupivacaine hydrochloride (low-quality evidence).

Dexmedetomidine is an α2-adrenoreceptor agonist. Its pain-relieving effects are believed to be mediated by α2-receptor binding on the spinal cord and central α2-receptors. The transmission of pain is inhibited by hyperpolarization of interneurons and a decline in the release of pronociceptive transmitters like glutamate and substance P.  The mechanisms underlying dexmedetomidine's pain-relieving effects are still not entirely known. It might be partly due to altered perception and decreased anxiety. However, an opioid-sparing effect is reported, and there may be an effect when utilized with locoregional anaesthesia procedures.

The benzodiazepine midazolam is characterized by a short duration of action and the prompt onset of clinical effects. Similar to other benzodiazepines, its pharmacological action includes amnesia, sedation, sleep induction, and anxiolysis. Its antinociceptive effect is still not apparent. Few researchers noted significant findings in animal models. On the other hand, few studies reported no impact on pain decline when linked with other analgesics or sedatives. The utilization of caffeine (>100 mg) as an adjunct to common analgesic agents has been witnessed to offer a small but significant rise (5–10%) in the percentage of individuals experiencing pain alleviation. In this systematic review, caffeine showed superior efficacy to codeine in minimizing swelling. A similar outcome was noted in the studies comparing piroxicam with placebo.

Individuals frequently witness great satisfaction with dental implants, with little effect of pre-operatory anxiety and prosthetic complications with time. In comparison with placebo, some analgesics (dexamethasone, liposomal bupivacaine, lornoxicam, and ibuprofen) were linked with improved patient satisfaction. Dexamethasone and ibuprofen displayed comparable results. In one split-mouth trial, the enrolled subjects preferred transdermal diclofenac diethylamine when compared to oral diclofenac sodium. However, due to randomization and the deviations from the intended interventions, the findings may have been biased.

Within the limitations of this study, the use of analgesics seems to enhance the patient's overall satisfaction with dental surgery. Rescue medication incorporates drugs given to an individual when the investigational medical product's efficacy is unsatisfactory. Diminished requirement for rescue medication was attained with lornoxicam, ibuprofen, and dexamethasone in comparison with placebo. Analgesics may exhibit a variety of mild to moderate noxious effects that should be considered during the prescription of analgesic therapy.

No noxious effects were found when using lornoxicam, ibuprofen, and dexamethasone. The adverse effects noted with liposomal bupivacaine were reported to be similar to the standard of care. A more extraordinary occurrence of bleeding was noted in dexketoprofen trometamol recipients vs placebo recipients. To minimize the incidence of side effects, it is essential to assess an individual's medical history, pharmacological properties, the severity of the individual's expected pain, and potential interactions with concurrent medications during the prescription of analgesics.

This study indicates that administering analgesics may offer some advantages to manage post-surgery pain after dental implant placement. However, future robust research is warranted. Though the available literature yields specific analgesic protocols for dental pain, the specific evidence-based analgesic for dental implant operation are unclear. A large number of molecules and protocols  available in the literature and the vast surgical variability of the implantology practice prevent from offering indications about the best therapy to alleviate post-surgery pain. Therefore, additional investigation, including studies having an adequate sample size evaluating standardized implant approaches, is required to guide best management practices in this domain.