First posted November 21, 2000 Last updated May 14, 2013

Neuroanatomy of Pain


Section 1: Introduction
Section 2: Current Understanding of Pain Pathways
Section 3: Current Pain Management

Section 1


This essay will attempt to outline the current understanding of the pain pathway and a current consensus position on the management of acute post-operative pain, based on contemporary research into the neuroanatomy, physiology, pharmacology, and psychology of pain.

This essay is by David Nelson, MD, it may not reflect the opinions of the Editorial Board.


Pain, as a proper subject of scientific observation and study, has long been neglected by medical science. Perhaps, like death, it reminds us too much of our failures as physicians. Or perhaps, like sex, it was seen as too private or subjective a subject for objective analysis. Whatever the reason, pain was never mentioned as a topic in my medical school, residency, or fellowship training, and now, as an Associate Editor of a surgical journal (Journal of Hand Surgery), it disturbs me to observe that post-operative pain management has never been the subject of an article in my journal since it began in 1976. And this, despite the fact that it occurs as a consequence (dare we say complication?) of 100% of our surgical procedures! (Marks, 1973; Utting, 1978, Oden, 1989) Studies have shown that 50-80% of patients experience inadequate pain relief or suffer moderate or severe pain (Warfield, 1995). Since these studies were carried out at large medical centers with active pain management programs, the actual incidence is almost certainly higher. A prominent researcher has concluded that the consensus of international pain management specialists is that the majority of patients experience unsatisfactory pain relief. (Rawal, 1999). This is clearly unacceptable.

Pain is too important a topic to continue continue to be ignored. Pain is the main reason most patients seek the advice of a physician, and all of our surgical patients experience pain. The surgeon who fails to recognize the role that pain plays in the recovery after surgery, or even just the role that the mere anticipation of post-surgical pain plays in the mind of his surgical candidates, is sadly out of touch with their patients and with current medical understanding.

Pain has finally been recognized as a proper subject for medical research, and we are now out of our Dark Ages with respect to pain knowledge, in terms of neuroanatomy, physiology, pharmacology, and psychology. Two examples will suffice to demonstrate this progress. Neuroatomical research has provided an explanation for the fact a patient under general anesthesia and who experiences no pain at all, still experiences many of the effects of pain: increased heartrate, increased blood pressure, emotional disturbances, decreased renal function, respiratory supression, gastrointestinal suppression, increased systamic vascular resistance and increased cardiac work, increased myocardial oxygen consumption, increased risk of deep venous thrombosis, and immunological suppression (Rawal, op cit). Secondly, we now recognize that acute pain and chronic pain are distinct entities physiologically, neuroanatomically, and psychologically. Chronic pain is NOT just acute pain that occurs over a long period of time.

Progress in the scientific understanding of pain can dramatically altered the amount of pain our patients experience, if we will just apply it. There have been many published studies showing how application of this knowledge can result in dramatically decreased post-operative pain. One study has even shown how the clinical application of this knowledge resulted in 46.4% of hand surgery patients, in a 3 year, prospective study, did not take any narcotic pain medication in the 10 days following surgery. The main obstacles to the implementation of this knowledge are our ignorance of our ignorance and the too-prevelant fatalistic opinion of surgeons that pain is largely unavoidable and that "good" patients will just bear it.


Section 2


The initial concept of pain perception was quite simple: the pain signal directly excited a periperal nerve, synapsed at the spinal cord, and was perceived in the sensory cortex. There was no signal modulation, it just arrived in the brain as it came from the body.

Like much in the rest of medicine, it was found to be not that simple.


Neuroanatomical, physiological, psychological, and pharmacological research
has shown that the pain pathway is amazingly complex, in keeping with its evolutionary importance to the survival of the organism.

In addition, the pain signal is modulated at the site of the pain, at the dorsal horn, and in multiple areas of the central nervous system, both the spinal cord and the brain.

(an anatomically correct diagram is shown below)

The importance of understanding the true anatomy and physiology of the pain pathway, and each site of modulation, is that each part of the system is a potential site of intervention.

The current state of the art

The pain from a stimulus typical of an operative procedure would originate via two mechanisms: (1) pain signals are transduced in peripheral pain receptors, and (2) inflammation, modulated by leukotrienes, nerve growth factor, braykinin, and other cytokines, as well as prostaglandins, histimine, and hydrogen ions, as well as neurosignalling chemicals such as norepinehrine and neuropeptides, all cause both direct painful stimuli as well as lower the threshold in nocioceptor affereent peripheral terminals. The effect of the threshold lowering is that previously sub-threshold stimuli are now painful, and previously painful stimuli have a greater effect.

The afferent (incoming) pain signals reach the dorsal root ganglion, cross the synapse to a higher neuron horn of the spinal cord and connect in the dorsal horn with interneuron cells. This is far from a simple, passive, one-to-one transmission. The signal processing in the dorsal root ganglion and the dorsal horn is complex and only partly understood. There are many factors, including: (1) descending stimulatory (shown in yellow) and inhibitory (shown in purple) signals from the brain; (2) production, release, reception, and modulation of neurotransmitter substances; and (3) other, less well-defined processes that are postulated in order to explain clinical findings, but not yet proven. These processes are thought to be both excitatory and inhibitory.



Anatomic Diagram of Pain Pathways

The two processes of increased excitability at the peripheral pain transducer cell and at the dorsal horn are termed "wind-up", and explains why patients feel continuing or increasing pain even when the peripheral stimulus has been withdrawn or is decreasing.

The afferent (incoming) pain signal is passed up the spinal cord via the spinothalamic tract and first comes to the thalamus. The pain signal is then sent to multiple locations in the brain, not just the sensory cortex. The complexity of the interconnections in the brain, and the fact that the signal does not just go to the sensory cortex, is demonstrated by a phenomenon well-known to surgeons, as mentioned above: a patient under general anesthesia, who experiences no pain at all, still experiences an increased heartrate and increased blood pressure. These changes can easily be reversed by peripheral nerve blocks, despite the ongoing peripheral stimulus of surgery. Studies have also shown less obvious changes: post-operatively the patient will have emotional responses, decreased renal function, respiratory supression (particularly with thoracic or abdominal surgery), gastrointestinal suppression, increased systamic vascular resistance and increased cardiac work, increased myocardial oxygen consumption, increased risk of deep venous thrombosis, and immunological suppression.

The interconnections within the brain are complex, and include the sensory cortex, the limbic system (emotions), the frontal cortex, and others. Given the complexity of the known interconnections and the primitiveness of our investigational methods, it is highly likely that further interconnections will be discovered in the future.

Psychological Modulation

The phenomenon of psychological modulation of pain is well-known to each of us, even if we are not researchers in the field. Just as it is easy to get out of bed at 5 am to go fishing but hard to get out of bed at 8 to go to work, a headache that is a minor nuisance when we are having fun can be overwhelming when we think we have brain cancer. Pain is contextual, and it can arguably be said that ALL pain is contextual. To dismiss this reality with the phrase "it's all in their head" is to both deny the reality of being human and to deny the monumentous truth in the saying: it is in their head, in the many complex interconnections of neurons and neurotransmitters that we are just beginning to understand. Although we are at a loss to fully explain the psychological modulation of pain, we are not at a loss at how to use this modulation modality to the benefit of our patients.

Section 3

Current post-operative pain management can be divided into three phases, pre-operative, intra- operative, and post-operative.

Phase 1: Pre-operative

Management of post-operative pain must start pre-operatively (hence the website name, There are two areas for intervention, related to: (1) the psychology of the patient contemplating surgery, and (2) the fact that inflammation sensitizes nerve endings.

The psychological aspects of pain and its anticipation

The patient who is considering the possibility of having surgery is very well aware that surgery may involve a lot of pain. If the surgeon ignores this fact, it only serves to magnify the problem in the mind of the patient. Despite this, many surgeons do not discuss pain with their patients prior to surgery. Surgeons need to address their patients' concern directly and honestly. Doing so decreases the patient's experience of pain.

The patient contemplating surgery is under a great deal of psychological stress, for many realistic reasons. All major surgeries confront the patient with the possibility of death. In addition, disability, cost, loss of independence are frequently real concerns. This sets the stage for unrealistic magnification of fears of postoperative pain. Indeed, there is no direct correlation between nocioception and pain complaints (Rawal). Patient satisfaction with their surgeon is better correlated with the patient's impression of their physicians's concern about their pain than with the actual experience of pain itself (Rawal). The surgeon should discuss expected postoperative pain as a routine part of the discussion of the risks and benefits of surgery.

Pain enhanced by inflammation

Inflammation can increase pain independent of the direct experience of pain. Prostaglandins induced by tissue injury and inflammation in the region of the surgical site lower the threshold of pain receptors. Any sustained-release NSAID can be used, blocking this independant pain mechanism. (Recent evidence also suggests that antiinflammatory medication may have a central effect in addition to their well- recognized peripheral analgesic actions, so their use may be doubly indicated.) The advent of COX-2 specific antiinflammatory medications that spare the hemostatic mechanism (prostaglandin-mediated platelet aggregation) has prompted more surgeon to take advantage of the administration of these agents prior to surgery. Due to the relatively short onset of action (two to three hours for rofecoxib), these medications can be administered the morning of surgery. There is some question regarding the effect of antiinflammatories retarding bone healing, which is of special interest in spinal fusion surgery or total joint replacement requiring bony ingrowth for stabilization. Although there is contradictory evidence in animal models, there is no clear evidence for delayed healing based on human data. (see Einhorn, AAOS Oct 2002 Bulletin). One study of 2257 patients in the UK did find that NSAID use in the prior 12 months preceeding a fracture correlated with healing complications. The effect of a short course of NSAID use, on the order of two weeks or so, does not seem to be a problem.


Phase 2: Intra-operative

The greatest area of concentration of research into postoperative acute pain management has been in the intra-operative phase. Neural blockade has been demonstrated to be very effective for postoperative pain management for almost all types of surgery (Rawal,1989; Tong, 1999; Peng, 1999). The amazing fact is that the success of neural blockade goes beyond the simple interruption of the pain signal to the sensory cortex, and is explained by recent neuroanatomical research. Most surgeons are well aware of the fact that patients under general anesthesia, and therefore completely free from experienced pain, have an increase in heartrate and blood pressure when painful stimuli occur. It is now known that the noxious afferent impluses arrive not just via the spinothalamic tract to the somatosensory area of the cerebral cortex, but are also distributed throughout the brain by other cortical or subcortical pathways, including the spinoreticular and spinomesencephalic tracts. An additional mechanism is that descending inhibitory pathways may also be activated, leading to a modulation of the nociceptive activity in the spinal cord (Anders, 1989). Pain is perceived in more than just the somatosensory cortex; for instance, the frontal cortex is thought to be involved in the emotional part of the pain experience. (Anders, op cit). These new neuroanatomical findings help to explain the effects of pain causing decreases in immune function, disturbances in emotions (spinoreticular tract), and other responses in the absence of experienced pain. Neural blockade is effective for many reasons.

The types of neural blockade include: (1) spinal and epidural analgesia; (2) regional blocks, such as axillary or scalene blocks; (3) peripheral nerve blocks, targeting specific peripheral nerves that innervate the surgical site; and (4) local blocks to the specific tissues involved, such as the skin, the periosteum (for extremity surgery), and peritoneum (in abdominal surgery). The timing of the blocks can be before or after surgery.

Pre-incisional blocks

Pre-incisional blocks (local anesthetic injections to the site of the incision or nerve block anesthesia such as spinal or regional blocks) is the first step in the intraoperative management of pain, and have been shown to be very effective in both placebo-controlled and non-placebo- controlled studies [ref set 1, see end of essay]. Studies that did not show any positive effect using lower concentrations or doses of bupivicaine (Cameron, 1985). The basic concept is to prevent the pain signals from reaching the spinal cord or brain and contributing to the distributed response noted above.


Post-incisional blocks

Wound infiltration at the end of the surgical procedure is the second step in the intraoperative management of pain. Although spinal or regional blocks may seem to obviate the need for this step, in fact the pain relief that is experienced by the patient is thought to be enhanced by this method. The surgeon needs to approach this step with the same attention to detail as the operative portion of the procedure. If this step is thought of as a minor adjunct to the procedure, it is unlikely to be performed very effectively. The best criterion of the effect of wound infiltration is fairly straightforward and obvious: for extremity surgery, if the patient wakes up in the recovery room with pain, the infiltration was not done effectively. Wound infiltration has been shown to be effective in thoracic and abdominal procedures, but are not as effective as in extremity surgery. Studies that showed effectiveness required high-dose and high-volume local anesthestic in various layers (ie, peritoneum fascia, muscle, and subcutaneous)[ref set 2]. Post-incisional blocks can be done in several ways: (1) infiltration prior to the closure of the wound (paying attention to the periosteum or other deepest structures as well as to the subcutaneous layer ; (2) local or regional nerve blocks; and/or (3) placement of an indwelling catheter in one of the wound layers for intermittent injection or continuous infusion. These methods are not mutually exclusive, and actually are best done in combination (usually the first with either of the latter two).

Phase 3: Post-operative

The surgeon's participation in post-operative pain management has usually been to order morphine IM PRN, for inpatients, or to prescribe large quantities of oral narcotics, for outpatients. Rather than relieving pain, this approach has been characterized as a "barrier to effective postoperative pain relief." (Rawal, 1989). Several factors contribute to the ineffectiveness of this approach, including fluctuating blood levels that may result in oversedation. Another is the surgeon's misconception that his role in post-operative pain management has been completed once the post-operative orders have been written. Oral, PRN medication needs to be appropriate in type and frequency to the specific pain being treated, and are only part of a complete perioperative pain management program.

Few surgeons evaluate the effectiveness of their pain management program. While evaluation of surgical outcomes is de rigour, effectiveness of pain management is the opposite: it is never done. Indeed, most surgeons' only perception of the effectiveness of their pain management is the number of times that they have gotten a telephone call from a patient on a weekend asking for more medication. Would it not be fair to say that that describes you? Rather than leading to effective pain management, this guarantees that 100% of the patients are given more pain medication than 100% of the patients need. In one study of a five-member hand surgery group, over a nine-month period in which 30 opioid pills were given for post-operative pain management, 4,639 opioid pills were prescribed but never used.



Anders E, Ryder-Rinder M, Pain mechanisms: anatomy and physiology; in Management of acute and chronic pain, Rawal N, ed.

Cameron AEP, Cross FW, : Pain and mobility after inguinal herniorrhaphy: Ineffectiveness of subcutaneoud bupivacaine. Br J Surg 72: 68-69, 1985.

Marks, Ann Int Med, 1973; cited in Rawal, chap 3, Management of acute and chronic pain, 1989.

Utting, Anesthesia, 1978; cited in Rawal, chap 3, Management of acute and chronic pain, 1989.

Peng PWH, Chan VWS: Local and regional block in postoperative pain congtrol. Surg Clin N Am, 79:2:345-370, 1999.

Rawan N. :Postoperative pain and its management. In: Management of acute and chronic pain, Rawan N,editor. BMJ Books, 1989, London.

Tong D, Chung F: Postopeartive pain control in ambulatory surgery. Surg Clin N Am, 72:2:401-430, 1999

Uden,Anesth Clin North Am 1989; cited in Rawal, chap 3, Management of acute and chronic pain, 1989.

Warfield CA, Kahn CH: Acute pain management: Programs in US hospitals and experineces and attitudes amound US adults. Anesthesiology 83: 1090-1094, 1995.


Other reference notes

ref 155 in Peng and chan:Tetzlaff JE, Andrish J, O'Hara J, et al: Effectiveness of bupivacaine administered via femoral nerve catheter for pain control after anterior cruciate ligament repair. J Clin Anesth 9:542-545, 1997

Ref set 1 [Bays RA, Barry L, Vasilenko P: The use of bupivacaine in elective inguinal herniorrhaphy as a fast and safe technique for relief of postoperatieve pain. Surg Gynecol Obstet 173: 4333-437, 1991. Hashemi K, Middleton MD: Subcutaneous bupivacaine for postoperative analgesia after herniorrhaphy. Ann R Coll Surg Engl 65:38-39, 1983. Holst P, Erichsen CJ, Dahl JB:et al: Effects of lidocaine aerosol versus placebo on postoperative pain and wound tenderness following minor gyneacological laparotomy. Acta Anaesthesiol Scand 36: 112-114, 1992. Johansson B, Hallerback B, Stubberod A, et al.: Preoperaative local infiltration with ropivacaine for postoperative pain relief after inguinal hernia repair: A randomized controlled trial. Dur J Surg 163:371-378, 1997.Owen H, Galloway DJ, Mitchell KF: Analgesia by wound infiltration after surgical excision of benign breast lumps. Ann R Coll Surg Engl 67:114-115, 1985 Sinclair R, Cassuto J, Hogstrom S, et al.: Topical anesthesia with lidocaine aerosol in the control of posteoperative pain. Anesthesiology 68:895-901, 1988 Trotter TN, Hayes-Gregson P, Robinson S, et al: Wound infiltration of local anesthetic after lower segment Caesarean section. Anesthesia 46:404-407, 1991 Tverskoy M, Cozacov C, Ayache M, et al: Postoperative pain after inguinal herniorrhaphy with different types of anesthesia. Anesth Analg 70:29-35, 1990.]

ref set 2:[Adams WJ, Avramovic J, Barraclough BH: Wound infiltration iwth 0.25% bupivacaine not effective for postoperative analsgeia after cholecystectomy. Aust N Z Surg 61:626-630, 1991 Patel JM, Lanzafame RJ, Williams JS, et al: The effects of incisional infiltration of bupivacaine hydrochloride upon pulmonary functions, ateletasis and narcotic need following elective choleystectomy. Surg Gynecol Obstet 157:338-340, 1983 ChesterJF, Ravindranath K, White BD, et al: Wound infiltration with bupivacaine: Objective evidence for efficacy in postoperative pain relief. Ann R Coll Surg Engl 71:394-396, 1989 Egan TM, Herman SJ, Doucette EJ, et al: A randomized controlled trial to determine the effectiveness of fascial infiltration of bupivacaine in preventing respiratory complications after elective abdominal surgery. Surgery 104:734-740, 1988 Gibbs P, Purushotham A, Auld C, et al: Conotinuous wound perfusion with bupivacaine for postoperative wound pain. Br J Surg 75:923-924, 1988 Johansson B, Glise H, Hallerback B, et al: Preoperative local infiltration with ropivacaine for posteperative pain relief after cholecystectomy. Anesth Analg 78:210-214, 1994 Levack ID, Holmes JD, Robertson GS: Abdominal wound perfusion for the relief of postoperative pain. Br J Anaesth 58:615-619, 1986 Partridge BL, Astagbile BE: The effects of incisional bupivacaine on postoperative narcotic requirements, oxygen saturation and length of stay in the post-anaesthetic care unit. Acta Anesthesiol Scand 34A:486-491, 1990 Pfeiffer U, Dodson ME, Van Mourik G, et al: Wound instillation for postoperative pain relief: A comparison between bupivacaine and saline in patients undergoing aortic surgery. Ann Vasc Surg 5: 80-84, 1991 Thomas DFM, Lambert WG, Lloyd Williams K: The direct perfusion of surgical wounds with local anaesthetic solutions: An approach to postoperative pain? Ann R Coll Surg Engl 65:226-229, 1983 van Raay JJAM, Roukema JA, Lenderrink BW: Intraoperative wound infiltrationwith bupivacaine in patients undergoing elective cholecystectomy. Arch Surg 127: 457- 459, 1992]


David L. Nelson, MD

November 18, 2001