In the last 20 years, perioperative pain management has gained utmost importance, not at least because patient satisfactions parallel has risen to an absolute priority in health care systems. However, perioperative pain management in neurosurgical patients (especially the intracranial procedures) continues to be a gray area due to the existing controversies and lack of consensus regarding the standardized treatment. Many therapeutic recommendations are still based on anecdotal case reports and show a questionable success. However, in contrary to the earlier belief that the pain following intracranial surgery is minimal, some newer data suggest the exact opposite, so that newer and more scientifically based treatment modalities have to be taken into account (1).

Importantly, on the one hand, neurosurgical patients form a unique subgroup in which systemic manifestation of poorly controlled pain may negatively impact on the hemostasis and cerebral hemodynamics, therefore, leading to devastating conditions (2–4). On the other hand, overzealous use of analgesics can also affect the rapid neurological assessment and may result in increased morbidity (2–4). Besides these facts, the literature related to postoperative pain management in neurosurgical patients is mainly limited to the pharmacological aspects; however, the role of other conditions including the size of the incision, underlying pathology, surgical factors/methods used, experience of the surgeon, assessment tools used, and preoperative and intraoperative factors should also be emphasized to give a more balanced view of the topic.

In the last years, there could be found several controversies in the perioperative pain management of neurosurgical patients. This narrative review primarily aims to elucidate and summarize these various perioperative factors related to pain incidence and intensity in adult craniotomy procedures to give a basis for better and especially more differentiated clinical decisions in perioperative pain management.

On the contrary to general belief, patients underwent a craniotomy experienced a substantial amount of pain both in occurrence and intensity (2). Post-craniotomy pain incidences are reported from 30 to 90%, depending upon various perioperative factors (4–9). This significant variation is multifactorial and also represents a lack of well-organized prospective epidemiological studies in this domain (6). The majority of post-craniotomy pain incidences were reported with 48 h of surgery (6). Though the severity of pain declines as the time passes, there can still be a peak of moderate to severe pain on the second postoperative period (10, 11). In the same report, the pain in first 24 h postoperatively was observed in 93% of patients, and the severe pain was absent after the eighth postoperative day. Indeed, the moderate to severe pain can be found in approximately half of the patients after an hour of procedure (2). The incidence subsequently decreased 3% for each year of life (12). The impact of pain after a craniotomy has been variously reported due to non-uniformity in defining craniotomy pain and the surgical approaches. Strikingly, the site-specific craniotomy pain (acoustic neuroma surgery) is also described and presents in a significant number of postoperative patients (4, 5, 13). Rimaaja et al. reported 64% incidence of such pain and about one-third of patients revealed both pre- and postoperative headache (13). Post-craniotomy pain after supratentorial craniotomy ranges from 17.5 to 29.3% (14–16). Also, the reported incidence of a chronic headache after neurosurgery reduces with time after surgical intervention (14–17). This variation in incidence shows that, besides other perioperative complications, the headache has a unique feature, which has various origins.

The variability in incidence and diagnosis of post-craniotomy pain can be better understood by taking in account the anatomical structures involved. The neural supply of scalp is from branches from cervical plexus and trigeminal nerve (3, 18). The supraorbital and supratrochlear nerves and divisions of the frontal nerve (ophthalmic division of trigeminal nerve) innervate the anterior portion of the scalp (3, 18). The zygomaticotemporal (maxillary division of trigeminal nerve), temporomandibular, and auriculotemporal nerves (mandibular division of trigeminal nerve) supply the temporal scalp (3). The cervical plexus branches, including greater auricular, and the greater, lesser, and least occipital nerves innervate the occipital scalp. The branches accompanying meningeal arteries innervate the dura mater. The free nerve endings and nociceptors are responsible for pain (3). Mechanical nociceptors that are connected to myelinated A-delta afferent nerve fibers (fast conducting, low threshold for activation) are activated with a stimulus-like sharp, pricking in nature. The unmyelinated, slow C-fibers are activated by mechanical, chemical, and cold–hot stimuli via polymodal nociceptors (3). There are several inflammatory/nociceptive mediators that regulate the pain type, origin, and intensity. It is still a complex and poorly understood phenomenon that some patients in comparison to others exhibit profound pain. Whether or not the amount or types of mediators play important role in this context is yet to be explored. The role of pharmacogenomics in post-craniotomy pain is another area of future research.

The craniotomy pain is primarily somatic and originates from the scalp, pericranial muscles, and soft tissue. The manipulation of the dura mater during surgical intervention also activated pain pathway (6). The physical stimulation caused by incision and traction utilized in craniotomy stimulates nervous terminals and specific nociceptors resulting in postoperative pain. The post-craniotomy pain is usually localized to the incision site and surrounding soft tissues. The generalized diffuse headache usually originates from dura (9, 14). The nature of pain after craniotomy is pulsating or usually pounding (19). The constant and continuous nature of pain is infrequently seen.

The persistent post-surgical pain after craniotomy is observed in many patients, and the proposed hypothesis includes dural irritation, pericranial muscle retraction, surgical trauma, decreased cerebrospinal fluid pressure, and aseptic meningitis (4). The patient position during the surgical intervention may lead to persistent tension headache and neck muscle spasm with possible muscular origin (19). For example, the mechanism of chronic persistent pain after acoustic neuroma resection is related to adherence of the dura to overlying muscles and has been related to surgical closure techniques (4, 20). Given such etiology for persistent pain, modified surgical closure such as replacement of the bone flap during the retrosigmoid approach to resection of vestibular schwannomas has been advocated. Such a modification has been found to reduce the rate of chronic headaches from 94 to 27% (5). Other modifications include fat grafting during closure with reduction of pain incidence from 30 to 12% (21). The role of cranioplasty with methyl methacrylate instead of craniectomy is controversial with regard to resolution of persistent pain (22, 23). Interestingly, in one study, more than 45% of post-craniotomy patients showed a headache during dental evaluation (17). These patients revealed tenderness around masseter muscles, and opening the mouth and jaw protrusion were the inciting events for a headache (17).

The literature shows that there is not one nature of postoperative pain, but there are several, sometimes small, conditions that contribute to such an event so that the variations of expressions of the pain can be explained.

Factors such as the surgical site and technique, nature of the surgical intervention, gender, tumor type and size, muscle resection, and use of steroids have been studied for their association with incidence and severity of pain (2, 4). The literature reports are conflicting and inconclusive.

Pain is known to have its impact on all body systems and organs. Cardiovascular effects include an increase in pulse rate and blood pressure. Hemodynamic fluctuations are undesirable during craniotomy procedures (37, 38). The precipitating factors for inducing sympathetic nervous activity have been correlated with plasma catecholamine concentrations as a surrogate marker (39). Hypertension during craniotomy is commonly associated with increased norepinephrine levels and activation of the renin–angiotensin–aldosterone system (39, 40). Fluctuations in blood pressure in patients with impaired cerebral autoregulation may impact cerebral blood flow and thus perioperative morbidity and mortality (4). Such hemodynamic fluctuations are frequently observed during scalp incision, periosteal detachment, dural opening, and brain retraction (38, 41, 42). This mandates in time hemodynamic stabilization for neurosurgical procedures and optimal pain management. Thus, appropriate management can help to reduce the rate of various adverse reactions and complications of surgery including hemorrhage, premature aneurysmal rupture, and cerebral ischemia caused by suboptimal pain control and hemodynamic fluctuations. The other associated problem with poor pain management is to use more opioids, which in turn increases the risk of postoperative nausea and vomiting. In addition, the inadequate control may also cause increased chances of postoperative cognitive dysfunction, agitation, and delirium. Importantly, these postoperative problems are usually seen as complications of neurosurgery and often; the pain management for such patients does not receive immediate attention.

It is evident that the common perception of the post-craniotomy pain is changing, and indeed, it is a severe postoperative problem that is sometimes difficult to manage as well. However, in-depth understanding of various perioperative factors related to pain occurrence and intensity can impart better patient’s management. Future investigation should reveal such factors in more detail through the well-designed studies.

TC and RG have given substantial inputs for developing the concept, design, data collection, synthesis, interpretation, and writing the manuscript. VS and LV have given important inputs for developing the concept and design and writing the manuscript. SB, RC, and BS have assisted in writing and editing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.