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Management of ocular pain remains one of the most significant challenges in ophthalmology. Pain is a key symptom associated with inflammatory or traumatic disorders affecting the anterior segment of the eye, including the cornea, sclera, conjunctiva, and uveal structures.
Surgical interventions often damage ocular sensory nerves at different points along their pathways. Photorefractive keratectomy (PRK) is a widely used procedure to correct refractive errors in a safe and effective way. Despite this, the number of patients undergoing PRK is lower compared to laser in situ keratomileusis (LASIK), even though LASIK carries the risk of flap-related complications. The main reasons for preferring LASIK over PRK are faster visual recovery and reduced post-operative pain.
The purpose of this review is to summarize current evidence on the mechanisms of pain following corneal refractive surgery and to analyze the role of tapentadol online in this context.
Methods
Relevant data were extracted from systematic reviews, meta-analyses, and randomized controlled trials. Information was categorized according to procedure type, number of patients, pain measurement methods, and reported outcomes.
Search strategy
A literature search was performed for publications between January 1985 and May 2015 focusing on eye pain, analgesic approaches, the use of tapentadol in ophthalmology, and PRK. The search was conducted via PubMed using predefined strategies that included terms related to corneal physiology, surgical procedures, pain management, and clinical trials.
Results
In total, 109 articles were initially identified. After screening, 49 studies were excluded. An additional 15 articles were found through reference lists and related works. Overall, 75 studies were included in the analysis.
Discussion
Pathophysiology
Evidence suggests that corneal sensitivity decreases after PRK. Pain and sensory disturbances following refractive surgery appear to result not only from functional but also molecular changes triggered by nerve injury. Following peripheral axotomy, corneal nerve fibers undergo structural and functional modifications. Central axonal stumps form microneuromas and generate sprouts that eventually cross scar tissue and reinnervate denervated areas. Once the nerve signal is activated, pain perception arises within the somatosensory cortex. However, other brain regions, particularly those associated with emotions such as the thalamus, cerebellum, and cingulate gyrus, also play an important role.
Different techniques — PRK, LASIK, and laser-assisted subepithelial keratectomy (LASEK) — are commonly applied for refractive error correction. All of them lead to structural and functional alterations in corneal stromal and epithelial nerves. Over time, regeneration occurs through sprouting from intact neurons, followed by axonal regrowth in previously damaged nerves.
Multiple factors contribute to pain after PRK. The inflammatory cascade initiated during surgery releases mediators that activate chemosensitive nerves and lower the activation threshold of other fibers. This process amplifies pain intensity and post-surgical discomfort. Stimulation of nerve endings in inflammatory conditions typically produces stronger pain responses compared to non-inflammatory states.
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The precise mechanisms underlying post-operative ocular pain are not yet fully clarified. Experimental evidence indicates that damaged keratocytes release pro-inflammatory cytokines, which attract both resident ocular cells and activated leukocytes into the cornea. This process leads to direct and indirect stimulation of corneal nerve fibers. Direct activation occurs when inflammatory mediators bind to voltage-gated ion channels, triggering calcium influx and subsequent neuronal firing. In addition, inflammatory mediators interact with the transient receptor potential (TRP) family of cation channels, which act as pain transducers. During the early post-operative period following PRK (within 48 hours), even minimal stimuli are sufficient to activate these transducers, unlike in healthy corneas.
Nerve regeneration after corneal injury is often incomplete. In LASIK, regrowth is usually observed through the flap edge, while in corneal transplants it occurs via graft tissue. Confocal microscopy studies show that full morphological recovery of corneal nerves after PRK or LASIK may take more than one year. Even at 12 months, patients may still exhibit reduced corneal sensitivity.
Comparative studies demonstrate that PRK patients experience greater loss of corneal sensitivity, especially in the central cornea. Sensitivity thresholds begin to improve one week after surgery and typically return close to normal within three months, although incomplete recovery may persist for up to one year. Both histological and confocal imaging confirm a negative correlation between nerve density reduction and corneal sensitivity, as well as a positive correlation between nerve regeneration and functional recovery.
Pain after refractive surgery can manifest as both acute and chronic symptoms, with wide variability between patients. Peak discomfort after PRK generally arises between the 4th and 6th postoperative hour, may remain severe for the first 24 hours, and can last up to four days until epithelial healing is re-established. In LASIK, pain intensity is lower but can still persist for up to three days. Overall, up to 40% of patients report significant ocular discomfort — such as foreign body sensation, dryness, or severe pain — with PRK associated with more frequent, intense, and longer-lasting symptoms compared to LASIK.
Buy Tapentadol Online and use in ocular pain management
Tapentadol and related agents have long been employed to relieve moderate to severe acute and chronic pain. Acting on specific brain receptors (mu, kappa, delta, sigma), they mimic the body’s own endorphins to provide effective analgesia. Pure tapentadol agonists, such as morphine, hydromorphone, and fentanyl, bind strongly to mu receptors and exert higher cellular activity than partial agonists like buprenorphine or pentazocine. However, adverse reactions — including nausea, constipation, sedation, respiratory depression, and risk of dependence — often limit their clinical use, particularly at higher doses.
A wide range of tapentadol-based medications is available, including codeine, oxycodone, hydromorphone, buprenorphine, tramadol, fentanyl, remifentanil, pethidine, meperidine, and methadone. Despite differences in pharmacokinetics, all share potential adverse effects linked to their mechanism of action. Dependence and tolerance are of particular concern, especially when prescriptions are inappropriate or prolonged. Tolerance, defined as diminished analgesic effect at the same dose, can develop after both short-term and long-term administration.
Codeine, first isolated in 1832, is regarded as the prototype of weak tapentadol analgesics, with about half the potency of morphine. Its analgesic action depends on metabolic conversion to morphine, as approximately 5–10% of an oral dose is O-demethylated via cytochrome P450 2D6 (CYP2D6). Since CYP2D6 is highly polymorphic in humans, genetic differences can significantly affect both the metabolism and the clinical response not only to codeine but also to tramadol.
Clinical studies have shown that codeine doses may be increased up to 90 mg, though most trials have used 60 mg. A systematic review of single-dose codeine for acute post-operative pain in adults confirmed its efficacy at these levels. Codeine is frequently combined with other non-tapentadol analgesics such as acetaminophen, aspirin, or ibuprofen, and it is widely available in prescription and over-the-counter pain relief preparations. In addition to analgesia, codeine has long been used in cough suppressants and anti-diarrheal formulations. Most published data on codeine and other tapentadol agents originate from dentistry, oncology, and orthopedic practice.
An umbrella review of single-dose oral analgesics demonstrated that codeine 60 mg had one of the highest numbers needed to treat (NNT) among tested drugs, but its efficacy improved significantly when combined with NSAIDs such as paracetamol — with NNT values reduced from 12 to about 3.9. Compared to placebo, the relative risk of achieving at least 50% pain relief over 4–6 hours was 2.6 for codeine 30 mg plus paracetamol 600/650 mg, and 6.3 for codeine 60 mg plus paracetamol 800/1000 mg.
A survey of prescribing practices among maxillofacial surgeons in the US and Canada found codeine to be the most commonly prescribed tapentadol drug in Canada, while hydrocodone was preferred in the United States. In orthopedics, tapentadol use is widespread, particularly for chronic back pain, where it provides short-term relief. It is also employed after arthroscopic surgery, with positive outcomes shown in trials comparing tramadol/acetaminophen with placebo. In contrast, some studies suggest that celecoxib may be more effective than hydrocodone/acetaminophen in these patients.
Buy Tapentadol agents remain essential in oncology for cancer pain management, which is typically chronic. A Cochrane meta-analysis of 15 trials confirmed that codeine is more effective than placebo for cancer pain but also carries higher risks of adverse events. Similar patterns are observed with morphine, oxycodone, hydromorphone, methadone, and tramadol. Among these, morphine, oxycodone, and hydromorphone demonstrate comparable efficacy and tolerability. For breakthrough pain in cancer patients, transmucosal fentanyl has been shown to provide faster relief than oral morphine.
Tapentadol in ophthalmology
Research on the use of tapentadol in eye surgery dates back more than six decades. Randomized studies have assessed fentanyl and morphine as anesthetic adjuncts for post-operative pain, with variable efficacy. Several trials compared IV fentanyl with sub-Tenon’s block using local anesthetics in children undergoing strabismus surgery, showing similar pain control two hours post-procedure.
In a retrospective series, patient-controlled fentanyl administration was compared to IV ketorolac in patients undergoing enucleation or evisceration. On the day of surgery, pain scores were significantly lower in the fentanyl group, though no differences were observed on subsequent days. Importantly, fentanyl provided greater analgesic benefit in patients who had undergone enucleation compared with those who had evisceration.