What do you think is happening with your jaw?

→Clicking Jaw

Sometimes your jaw makes a clicking sound when you open or close your mouth. This happens to many people and usually doesn’t hurt or need any treatment. This is called disc displacement with reduction.

→Jaw Doesn’t Open All the Way

This is when your jaw can’t open fully because the disc inside the joint is fully sitting in front of the joint. It might hurt when you try to eat or talk. You also might not be able to move your jaw side to side very well. This is called disc displacement with no reduction.

→Jaw Gets Stuck Sometimes

Your jaw might get stuck closed for a bit. This is more likely to happen in people with a history of clicking noise in front of the ear, with the occasional jaw being stuck closed on waking. It often fixes itself. This is called episodic locking.

→Jaw Pops Out of Place

This happens when you open your jaw too wide, and get stuck open. It happens because the joint moved out of the socket. Seizure, trauma to your face, or hyper flexible jaw joints can cause this more frequently. This is called TMJ luxation.

→Jaw Gets Stuck Open

Sometimes your jaw can get stuck open, but you can close it yourself. This happens when the jaw joint moves out of the disc but not necessarily the socket. This is called open locking.

Why to deliver a medication through the oral mucosa?

1. To avoid the stomach and first-pass elimination
2. To avoid the influence of the presence of food
3. Direct access to a lesion or condition
4. Quick absorption

Intraoral Permeability

The oral mucosa is not a uniformly, highly permeable tissue like the gut, but shows regional variation. The keratinized areas (thicker), such as gingiva and hard palate, are least permeable and nonkeratinized lining areas (such as the tissue under the tongue) are most permeable. (Squier 1991)

Holding medication in place!

One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. (Sohi et al, 2010)

Technological advances in mucoadhesive, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases.  (Hearnden  et al, 2011)

It is possible to use a tissue coverage with an appliance similar to a bleaching tray. These oral appliances, whether used alone as a physical barrier or as a vehicle to deliver topical anesthetic, represent a safe and effective modality for the management of neuropathic orofacial pain disorders. (Bavarian  et al, 2022)

References

Sheikh S, Gupta D, Pallagatti S, Singla I, Gupta R, Goel V. Role of topical drugs in treatment of oral mucosal diseases. A literature review. N Y State Dent J. 2013 Nov;79(6):58-64. PMID: 24600767.

Squier CA. The permeability of oral mucosa. Crit Rev Oral Biol Med. 1991;2(1):13-32. doi: 10.1177/10454411910020010301. PMID: 1912142.

Kurosaki Y, Kimura T. Regional variation in oral mucosal drug permeability. Critical reviews in therapeutic drug carrier systems. 2000;17(5):467-508.

Sohi H, Ahuja A, Ahmad FJ, Khar RK. Critical evaluation of permeation enhancers for oral mucosal drug delivery. Drug Dev Ind Pharm. 2010 Mar;36(3):254-82. doi: 10.1080/03639040903117348. PMID: 19663558.

Hearnden V, Sankar V, Hull K, Juras DV, Greenberg M, Kerr AR, Lockhart PB, Patton LL, Porter S, Thornhill MH. New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev. 2012 Jan;64(1):16-28. doi: 10.1016/j.addr.2011.02.008. Epub 2011 Mar 1. PMID: 21371513.

Bavarian R, Khawaja SN, Treister NS. Oral appliances in the management of neuropathic orofacial pain: A retrospective case series. Oral Dis. 2022 Apr;28(3):805-812. doi: 10.1111/odi.13824. Epub 2021 Mar 9. PMID: 33650141.

1.Assess: Determine the language barrier early on. If you notice the patient or their companions struggling to understand, assume there might be a language barrier.

2.Simple Language: Speak slowly and clearly, using simple words and short sentences. Avoid using medical jargon or slang.

3.Visual Aids: Draw diagrams, use charts, or show pictures to help convey information about symptoms, treatments, or procedures.

4.Use Technology: Use translation apps or devices to help facilitate communication. There are many apps available that can translate spoken or written language in real-time.

5.Professional Interpreters: If available, utilize professional interpreter services. Hospitals and healthcare facilities often have access to interpreters either in person, over the phone, or via video conferencing.

6.Bilingual Staff or Family Members: If there are staff members who speak the patient’s language, or if the patient has family members who can interpret, involve them in the conversation.

7.Be Patient and Respectful: Communicating through a language barrier can take time and patience. Be respectful, understanding, and avoid getting frustrated.

8.Ask Simple Questions: Break down questions into simple, yes-or-no questions or multiple-choice options to make it easier for the patient to respond.

9.Confirm Understanding: After providing information or instructions, ask the patient to repeat or demonstrate their understanding to ensure clarity.

10.Written Instructions: Provide written instructions or educational materials in the patient’s language whenever possible. This can help reinforce verbal communication.

11.Cultural Sensitivity: Be aware of cultural differences that may affect communication and healthcare decisions. Respect the patient’s cultural beliefs and practices.

12.Follow-up: Schedule follow-up appointments or check-ins to ensure the patient is following treatment plans and to address any further questions or concerns.

13. Mind wordless cues: Visual facial expressions are very important. For example, you always smile at people and speak gently. If you’re giving confident wordless mark, at least it can make it seem like you’re friends.

14. Use gestures: This approach can be helpful when directing different languages as well. For example, when people who don’t speak the same language are thirsty, they point to a cup and their mouth. It helps them understand what they want to say.

15. Prepare the environment: The patient is definitely nervous because he is in an unfamiliar environment. Therefore, it is important to relax him. For example, you can play music from their country, or prepare a card in their country’s language that means you don’t have to worry.

DISCLAIMER:  Document partially created using OpenAI. (2024). ChatGPT (version 3.5) https://chat.openai.com/ 

Chewing gum is the choice of preference among all candy in most age groups, and although it is not ingested, it is considered a part of an individual’s regular diet.

Although this may seem like a normal and harmless habit, gum-chewing is considered a parafunction that causes inflammation of the temporomandibular joint, and fatigue and pain in muscles of mastication.

• Gum-chewing on a regular basis = pain, clicking and locking of the jaw.
• Gum-chewing for several hours a day = pain, clicking and locking of the jaw, swelling and stiffness of the muscles of mastication.

Chewing gum can also be associated with headaches and limited mouth opening. The type and quality of pain will depend on the number of hours and type of chewing. If after chewing gum, the limit of pain has been reached, it can be treated with heat or ice, as well as over the counter medications like NSAIDS to decrease pain and inflammation.

There is enough evidence to support the idea of gum-chewing causing TMJ pain and headaches; ideally, gum should be eliminated entirely from a lifestyle.

References:

1. Tabrizi R, Karagah T, Aliabadi E, Hoseini SA. Does gum chewing increase the prevalence of temporomandibular disorders in individuals with gum chewing habits? The Journal of craniofacial surgery. 2014;25(5):1818-1821. doi:10.1097/SCS.0000000000000993
2. Martyn DM, Lau A. Chewing gum consumption in the United States among children, adolescents and adults. Food additives & contaminants Part A, Chemistry, analysis, control, exposure & risk assessment. 2019;36(3):350-358. doi:10.1080/19440049.2019.1567944
3. Mejersjö C, Ovesson D, Mossberg B. Oral parafunctions, piercing and signs and symptoms of temporomandibular disorders in high school students. Acta odontologica Scandinavica. 2016;74(4):279-284. doi:10.3109/00016357.2015.1114668
4. Olchowy C, Grzech-Leśniak K, Hadzik J, Olchowy A, Łasecki M. Monitoring of Changes in Masticatory Muscle Stiffness after Gum Chewing Using Shear Wave Elastography. Journal of clinical medicine. 2021;10(11):2480-. doi:10.3390/jcm10112480
5. Lippi G, Cervellin G, Mattiuzzi C. Gum-Chewing and Headache: An Underestimated Trigger of Headache Pain in Migraineurs? CNS Neurol Disord Drug Targets. 2015;14(6):786-90. doi: 10.2174/1871527314666150225143105. PMID: 25714969.

What can I do to help my jaw pain?

Temporomandibular disorders affect the temporomandibular joint, and muscles of mastication. The cause of this phenomenon is multifactorial, and can be associated with occlusal conditions, stress, trauma, and parafunction. Unfortunately, this disorder is irreversible; however, on the day-to-day basis, by restricting behaviors, any pain associated to the inflammation of the joints and surrounding muscles can decrease, as well as intercept further degeneration.

Basic in-home treatment:

• Diet: soft and in small bites, slow chewing; avoid gum.
• Teeth contact: disengage if in contact during other situations that do not involve chewing or speaking.
  • Tip: release a small puff of air and retain position.
• Avoid wide mouth-opening (cut food into pieces, press any food that requires large bites; yawn with limitation: place hand under chin, or move chin towards neck to limit opening.
• Find awareness of parafunctions: biting objects, clenching, grinding, and stop.
• Massage therapy: circular movements and pressure against the muscles until producing warmth, enhancing the blood flow in soft tissues – twice a week, 30 minutes per session.
• Thermotherapy: moist heat for 20 minutes a day in the affected regions.
• N-stretching exercises: tip of the tongue against palate (simulating letter “n”), open wide without removing tongue from the original position and hold for 6 seconds. This should be six times per session, and six times a day.

The purpose of general avoidance is to lessen joint pressure, regain muscle length, and decrease muscle activity.

Simple rule to follow: “if it hurts, don’t do it.”

References:

1. Liu F, Steinkeler A. Epidemiology, Diagnosis, and Treatment of Temporomandibular Disorders. The Dental clinics of North America. 2013;57(3):465-479. doi: 10.1016/j.cden.2013.04.006
2. Okeson, Jeffrey P., Management of Temporomandibular disorders, and occlusion, eighth edition, Elsevier, 2020.
3. Wieckiewicz M, Boening K, Wiland P, Shiau YY, Paradowska-Stolarz A. Reported concepts for the treatment modalities and pain management of temporomandibular disorders. J Headache Pain. 2015; 16:106. doi: 10.1186/s10194-015-0586-5. Epub 2015 Dec 7. PMID: 26644030; PMCID: PMC4671990.
4. Kraaijenga S, van der Molen L, van Tinteren H, Hilgers F, Smeele L. Treatment of myogenic temporomandibular disorder: a prospective randomized clinical trial, comparing a mechanical stretching device (TheraBite®) with standard physical therapy exercise. Cranio. 2014;32(3):208-216.

Opioids

Opioids are very potent and effective drugs; they are traditionally used for both acute and chronic pain conditions. However, opioids commonly cause vigorous side effects, some of which are likely to become lethal.

The opioid signaling system has the greatest receptor for tolerance development; consequently, requiring some cases to increase the intake amount of the drug to fulfill the analgesic effect.

Opioid Induced Hyperalgesia (OIH)

Opioid induced hyperalgesia (OIH), is defined as a heightened response to painful stimuli, caused by opioid consumption.

This manifests as either hyperalgesia (increased/extreme sensitivity to pain), or allodynia (pain caused by stimulus that normally does not provoke pain); it becomes more intense while the dose and exposition duration are increased. The outcome varies according to characteristics of each patient.

Diagnosis

OIH is difficult to recognize due to the variation of symptoms among patients, resulting in a diagnosis of exclusion. It should not be the first diagnosis of any case, even if the patient has been on long-term opioid treatment.

Clinicians should suspect OIH when opioid effect decreases, without disease progression, especially if there is unexplained pain reports or allodynia unassociated with the original pain, and increased pain with increasing dosages.

Common opioids

The opioids used, in order of frequency, are morphine, fentanyl, oxycodone, hydromorphone, and methadone. The administration can vary in all forms: oral, intravenous, transcutaneous, transmucosal, and intrathecal.     

Management

Opioid cessation, opioid rotation, and auxiliary pharmacotherapies, such as ketamine and dexmedetomidine. Adjuvant drugs appear to be the most effective approach in terms of absolute decrease in opioid use.

Opioid induced hyperalgesia can be resolved when this condition is diagnosed and managed.

• References
  1. Mercadante S, Arcuri E, Santoni A. Opioid-Induced Tolerance and Hyperalgesia. CNS Drugs. 2019 Oct;33(10):943-955. doi: 10.1007/s40263-019-00660-0. PMID: 31578704.
  2. Hayhurst CJ, Durieux ME. A Clinical Reality. Anesthesiology (Philadelphia). 2016;124(2):483-488. doi:10.1097/ALN.0000000000000963
  3. Turan A, Sessler DI. Opioid cessation: another teachable moment. Br J Anaesth. 2020 Sep;125(3):219-221. doi: 10.1016/j.bja.2020.05.004. Epub 2020 Jun 3. PMID: 32505336.
  4. Guichard L, Hirve A, Demiri M, Martinez V. Opioid-induced Hyperalgesia in Patients With Chronic Pain: A Systematic Review of Published Cases. The Clinical journal of pain. 2021;38(1):49-57. doi:10.1097/AJP.0000000000000994
  5. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011 Mar-Apr;14(2):145-61. PMID: 21412369

Saliva is of vital importance for the maintenance of oral health, including the lubrication and repair of oral tissues, oral acid neutralization, maintenance, enamel in children, tooth remineralization, digestion, and speech.

Systemic disorders can result in salivary gland dysfunction, for instance: Sjögren syndrome, diabetes, depression, head and neck radiotherapy, acquired immunodeficiency syndrome, etc. Nonetheless, the most common cause is the use of medications.

Medication induced hyposalivation increases the risk for oral diseases, such as: dental caries, candidiasis, bad breath, taste disturbances, difficulties in chewing, speaking, and swallowing.

Common medications that cause xerostomia are, but not limited to:

· Antibone-resorptives (osteoporosis)

· Anticonvulsants

· Antidementia

· Antidepressants

· Antihypertensives

· Antimigraine

· Antimuscarinics

· Antiparkinson

· Antiperistaltic

· Antipsychotics

· Appetite suppressants

· Diuretics

· Muscle relaxants,

· Opioid-analgesics

· Psychostimulant

· Sedatives

Prevention:

Gentle massage of the major salivary glands; adequate fluid intake; sugarless candies, wiping the oral cavity with glycerin swabs to stimulate salivary flow; sugarless antifungal agents such as nystatin powder or clotrimazole troches are recommended as well.

Treatment

Salivary-gland destruction is irreversible regardless of the method of damage. However, saliva substitutes are available as rinses and gels. Sipping water, as well as sugarless candy and chewing gum provide relief for some patients due to the taste and mechanical stimulation of salivation.

REFERENCES

1. Aliko A, Wolff A, Dawes C, et al. World Workshop on Oral Medicine VI: clinical implications of medication-induced salivary gland dysfunction. Oral surgery, oral medicine, oral pathology and oral radiology. 2015;120(2):185-206. doi:10.1016/j.oooo.2014.10.027

2. Barbe AG. Medication-Induced Xerostomia and Hyposalivation in the Elderly: Culprits, Complications, and Management. Drugs & aging. 2018;35(10):877-885. doi:10.1007/s40266-018-0588-5

3. Wolff, Joshi RK, Ekström J, et al. A Guide to Medications Inducing Salivary Gland Dysfunction, Xerostomia, and Subjective SIalorhhea: A Systematic Review Sponsored by the World Workshop on Oral Medicine VI. Drugs in R &D (Online). 2017; 17(1):1-28. Doi: 10.1007/s40268-016-0153-9

4. Grisius MM. XEROSTOMIA. 2nd. ed. Springer Publishing Company; 2008:821

Grid

My clicking jaw

Using a topical medication in the mouth!

Instructions for intraoral appliance use

How to overcome language barriers in a medical consultation:  tips for providers

Avoid chewing gum!

The basic home-protocol for TMD

Sleep hygiene means having both a bedroom environment and daily routines that promote consistent, uninterrupted sleep.

SUGGESTIONS FOR BETTER SLEEP

• Keeping a stable sleep schedule
• Making your bedroom comfortable and free of disruptions
• Following a relaxing pre-bed routine
• Building healthy habits during the day

CDC recommends some habits that can improve sleep health:

• Be consistent. Go to bed at the same time each night and get up at the same time each morning, including on the weekends
• Make sure your bedroom is quiet, dark, relaxing, and at a comfortable temperature
• Remove electronic devices, such as TVs, computers, and smartphones, from the bedroom
• Avoid large meals, caffeine, and alcohol before bedtime
• Get some exercise. Being physically active during the day can help you fall asleep more easily at night.

Mayo Clinic has the following advice:

• Stick to a sleep schedule
• Pay attention to what you eat and drink
• Create a restful environment
• Limit daytime naps
• Include physical activity in your daily routine
• Manage worries

References

Sleep Stages (by Kryger et al, 2017)

• Normal human sleep comprises two states—rapid eye movement (REM) and non–REM (NREM) sleep—that alternate cyclically across a sleep episode.
• Sleep begins in NREM and progresses through deeper NREM stages (stages 2, 3, and 4 using the classic definitions, or stages N2 and N3 using the American Academy of Sleep Medicine Scoring Manual definitions) before the first episode of REM sleep occurs about 80 to 100 minutes later.
• Thereafter, NREM sleep and REM sleep cycle with a period of about 90 minutes. NREM stages 3 and 4 (or stage N3) concentrate in the early NREM cycles, and REM sleep episodes lengthen across the night.
• Newborn humans enter REM sleep (called active sleep) before NREM (called quiet sleep) and have a shorter sleep cycle (about 50 minutes).
• NREM sleep slow waves are not present at birth but emerge in the first 2 years. Slow wave sleep (stages 3 and 4) decreases across adolescence by about 40% from preteen years and continues a slower decline into old age, particularly in men and less so in women.
• REM sleep as a percentage of total sleep is about 20% to 25% across childhood, adolescence, adulthood, and into old age, except in dementia.

The normal human adult enters sleep through NREM sleep, REM sleep does not occur until 80 minutes or longer thereafter, and NREM sleep and REM sleep alternate through the night, with about a 90-minute cycle.

• 75% of sleep is N-REM, 25% is REM
• N-REM has 4 stages.
  • 1 and 2 are light sleep.  2 is where bruxism is more prevalent
  • 3 and 4  are restorative sleep and is affected by age and chronic conditions such as fibromyalgia
• REM is suppressed by clonazepam.  It is reduced with age.

Links

Sleep stages:  https://www.verywellhealth.com/the-four-stages-of-sleep-2795920

References

Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Sixth edition. Elsevier; 2017.

There are multiple mechanisms for pain modulation (inhibition and facilitation).  Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain.  Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus  and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers.

INHIBITION

• Gate control theory
  • In 1965, Ronald Melzack and Charles Patrick (Pat) Wall (Melzack and Wall 1965) proposed the Gate Control Theory of Pain.  They proposed that the gate in the spinal cord is the substantia gelatinosa in the dorsal horn, which modulates the transmission of sensory information from the primary afferent neurons to transmission cells in the spinal cord. This gating mechanism is controlled by the activity in the large and small fibers. Large-fiber activity inhibits (or closes) the gate, whereas small-fiber activity facilitates (or opens) the gate.
  • The mechanism of the gate is influenced both by descending nerves and peripheral input.
  • Examples of gate control in pain are rubbing a painful area or using a TENS unit.
• Periaqueductal gray (midbrain) and Rostroventral medulla (PAG/RVM)
  • Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) and spinal cord dorsal horn, as a primary anatomical pathway mediating opioid-based analgesia.
  • The midbrain periaqueductal gray is a vital supraspinal site of the endogenous descending pain-modulating system.
  • The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors.
  • The PAG does not have a major projection to the spinal cord, and its role in the descending control seems to be exerted through pain modulating neurons located in the rostral ventromedial medulla (RVM), i.e. the nucleus raphe Magnus and adjacent structures.
  • Contributes with the release of inhibitory monoamines, serotonin and norepinephrine.
  • Main source of serotonin is nucleous raphe magnus.
  • Main source of norepinephrine is locus ceruleus.
  • Two types of RVM neurons have been shown to be involved in pain modulation, namely, off- and on-cells. Manipulations that cause off-cells to become continuously active and on-cells to become silent invariably produce analgesia.  Both off- and on-cells project to the dorsal horn.
  • PAG/RVM inhibits the release of excitatory neurotransmitters (CGRP and SP).
• GABA/Glycine
  • GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels.
• Reticular formation
  • The perception of pain is highly complex and requires neural integration from a variety of routes.
  • Spinal pathways to the amygdala, hypothalamus, reticular formation, medial thalamic nuclei, and limbic cortical structures transmit information involving arousal, bodily regulation, and emotional responses.
• Conditioned modulation
  • Diminution of perceived pain intensity for a test stimulus following application of a conditioning stimulus to a remote area of the body, and is thought to reflect the descending inhibition of nociceptive signals.
• Endogenous opioid system
  • Natural opioids are released in response to nociception (enkephalins, dynorphins and beta-endorphin).

FACILITATION

• Summation
  • Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity.
  • Spatial summation is a phenomenon in which repeated and equal-intensity noxious stimuli at a specific frequency cause an increase in the pain experienced.
• Upregulation
  • Increase in the number or density of cell surface receptors for a physiologically active substance, causing an increase in sensitivity in response to persistent exposure.
• Sodium channels upregulation means increased levels of transcription, subunit interaction or post-translational modification (notably glycosylation and phosphorylation).
• Although several peripheral ion channels are involved in nociceptive transmission, it is obvious that voltage-gated sodium channels are the most important. Normally, sensory neurons are relatively quiet but following tissue injury, the number of voltage-gated sodium channels is upregulated at the peripheral terminals of nociceptors. This accumulation of sodium channels can lower the threshold for creating an action potential resulting in hyperexcitability of primary nociceptors (peripheral or nociceptor sensitization). And with ongoing nociceptive input to second-order neurons in the trigeminal brainstem, it can also result in central sensitization, an important mechanism involved in many chronic pain syndromes including neuropathic pain.

References

1. Moayedi M, Davis KD. Theories of pain: from specificity to gate control. J Neurophysiol. 2013 Jan;109(1):5-12. doi: 10.1152/jn.00457.2012. Epub 2012 Oct 3. PMID: 23034364.
2. Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: Specificity, recruitment and plasticity. Brain Res Rev. 2009 Apr;60(1):214-25. doi: 10.1016/j.brainresrev.2008.12.009. Epub 2008 Dec 25. PMID: 19146877; PMCID: PMC2894733.
3. Loyd DR, Murphy AZ. The role of the periaqueductal gray in the modulation of pain in males and females: are the anatomy and physiology really that different? Neural Plast. 2009;2009:462879. doi: 10.1155/2009/462879. Epub 2009 Jan 28. PMID: 19197373; PMCID: PMC2633449.
4. Li P, Zhang Q, Xiao Z, Yu S, Yan Y, Qin Y. Activation of the P2X₇ receptor in midbrain periaqueductal gray participates in the analgesic effect of tramadol in bone cancer pain rats. Mol Pain. 2018 Jan-Dec;14:1744806918803039. doi: 10.1177/1744806918803039. Epub 2018 Sep 10. PMID: 30198382; PMCID: PMC6176534.
5. Taylor NE, Pei J, Zhang J, Vlasov KY, Davis T, Taylor E, Weng FJ, Van Dort CJ, Solt K, Brown EN. The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe: Separating Analgesia and Anxiety. eNeuro. 2019 Feb 19;6(1):ENEURO.0018-18.2019. doi: 10.1523/ENEURO.0018-18.2019. PMID: 31058210; PMCID: PMC6498422.
6. Tortorici V, Morgan MM, Vanegas H. Tolerance to repeated microinjection of morphine into the periaqueductal gray is associated with changes in the behavior of off- and on-cells in the rostral ventromedial medulla of rats. Pain. 2001 Jan;89(2-3):237-44. doi: 10.1016/s0304-3959(00)00367-5. PMID: 11166480.
7. Price DD. Central neural mechanisms that interrelate sensory and affective dimensions of pain. Mol Interv. 2002 Oct;2(6):392-403, 339. doi: 10.1124/mi.2.6.392. PMID: 14993415.