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Oftentimes, an anesthesia provider’s role involves helping patients with long-term pain management.¹ In fact, some anesthesia professionals specialize in managing chronic pain or do research to develop effective treatments for chronic pain.² Patients with long-lasting pain may take various types of drugs, including opioids.³ Chronic opioid use is accompanied by several side effects, such as tolerance and dependence, and recent research has focused on opioids’ effects on sleep.⁴ Before prescribing opioids for long-term use, anesthesia providers should be familiar with the effects of chronic opioid use, the definition of sleep apnea and the relationship between opioid therapy and sleep difficulties. 

Adverse effects of long-term opioid therapy include constipation, tolerance, endocrinopathies, sleep disorders, cognitive effects, respiratory depression, overdose and addiction.⁵ Data show a higher risk of overdose and death with increased daily opioid doses, particularly above the equivalent of 100 milligrams of oral morphine per day.⁵ While extended-release or long-acting formulations may be beneficial for patients using opioids for long periods of time, they may be associated with a higher risk for abuse due to their large dosages.⁵ Long-term opioid use can lead to hypogonadism, immunosuppression and increased risk of myocardial infarction.⁶ In addition, patients who use opioids frequently may develop tolerance and hyperalgesia (pain sensitivity), and may be at risk for complications during acute anesthesia.³ Though many patients may not develop opioid use disorder (OUD), the physical dependence from long-term opioid use can complicate attempts to wean off or discontinue opioid use.⁷ Evidently, chronic opioid use has many acute and long-lasting effects on a patient’s body. 

Opioids cause breathing to slow and become irregular,⁸ and this effect continues throughout chronic use.⁹ Apnea, which is temporary cessation of breathing, can be a risk for patients who use opioids over long periods of time.⁹ Sleep apnea is a potentially serious sleep disorder in which breathing repeatedly stops and starts.¹⁰ It is marked by loud snoring and exhaustion even after a full night’s sleep.¹⁰ The three main types of sleep apnea are obstructive sleep apnea (OSA), the most common form that occurs when throat muscles relax; central sleep apnea (CSA), which occurs when the brain does not send proper signals to the muscles that control breathing; and complex sleep apnea syndrome, also known as treatment-emergent central sleep apnea, which occurs when someone has both OSA and CSA.¹⁰ The general population has a high prevalence of OSA, which often goes undiagnosed.⁹ 

The combination of opioid use and potential for sleep apnea can create dangerous sleep issues for opioid-maintained patients.⁸ According to Pattinson, there had been few studies on the effects of opioids on breathing during sleep in humans when he wrote his review in 2008.⁸ Since then, however, many researchers have investigated the effects of opioids on respiration and sleep quality. Van Ryswyk and Antic’s review found a clear link between opioid use and sleep-disordered breathing (SDB), which affects the majority of chronic opioid users in a dose-dependent fashion.¹¹ Chowdhuri and Javaheri suggest that opioid-related SDB is related to binding to the pre-Bötzinger complex, hypoglossal nerve nucleus and chemoreceptor sites.¹² Ventilatory instability is especially prominent in opioid users during non-rapid eye movement (non-REM) sleep.¹² Chronic opioid users are also predisposed to CSA and, to a lesser extent, OSA.¹¹ Indeed, a review by Correa et al. showed that overall prevalence of CSA in patients taking chronic opioids was 24 percent.¹³ Opioid-related SDB is associated with poor sleep quality¹⁴ and risks of respiratory depression and even death.¹⁵ For patients who already have OSA, chronic opioid use may confer greater mortality risk.¹⁶ Treatments for opioid-related SDB, CSA and OSA include cognitive behavioral therapy, medication, positive airway pressure (PAP), oral devices and adaptive servo-ventilation (ASV).^11,14 However, more research is needed to evaluate long-term outcomes of PAP and ASV.^11,12 Also, there are limited data available on perioperative management of patients with opioid-related sleep apnea.¹³ 

Anesthesia providers who care for patients with chronic pain must be familiar with long-term opioid use and its consequences. Opioids can cause issues ranging from constipation to tolerance and psychological addiction. Chronic opioid use is also related to breathing issues during sleep, such as SDB, CSA and OSA, all of which can increase risk for respiratory depression and mortality. Further research is needed to establish the long-term effects of mechanical ventilation as a solution for opioid-related sleep issues. 

1.American Society of Anesthesiologists. Role of Physician Anesthesiologist. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/anesthesia-101/role-of-physician-anesthesiologist/. 

2.American Society of Anesthesiologists. Types of Pain: Chronic Pain. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/pain-management/types-of-pain/chronic/. 

3.Miclescu A. Chronic pain patient and anaesthesia. Romanian Journal of Anaesthesia and Intensive Care. 2019;26(1):59–66. 

4.Rosen IM, Aurora RN, Kirsch DB, et al. Chronic Opioid Therapy and Sleep: An American Academy of Sleep Medicine Position Statement. Journal of Clinical Sleep Medicine. 2019;15(11):1671–1673. 

5.Harned M, Sloan P. Safety concerns with long-term opioid use. Expert Opinion on Drug Safety. 2016;15(7):955–962. 

6.Chou R, Deyo R, Devine B, et al. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evid Rep Technol Assess (Full Rep). 2014(218):1-219. 

7.Rosenquist R. Use of opioids in the management of chronic non-cancer pain. In: Crowley M, ed. UpToDate. Alphen aan den Rijn, South Holland, Netherlands: Wolters Kluwer; October 1, 2019. 

8.Pattinson KTS. Opioids and the control of respiration. BJA: British Journal of Anaesthesia. 2008;100(6):747–758. 

9.Shafazand S. Sleep-disordered breathing in patients chronically using opioids. In: Eichler AF, ed. UpToDate. Alphen aan den Rijn, South Holland, Netherlands: Wolters Kluwer; January 22, 2020. 

10.Mayo Clinic. Sleep apnea. Diseases & Conditions July 25, 2018; https://www.mayoclinic.org/diseases-conditions/sleep-apnea/symptoms-causes/syc-20377631. 

11.Van Ryswyk E, Antic NA. Opioids and Sleep-Disordered Breathing. Chest. 2016;150(4):934–944. 

12.Chowdhuri S, Javaheri S. Sleep Disordered Breathing Caused by Chronic Opioid Use: Diverse Manifestations and Their Management. Sleep Medicine Clinics. 2017;12(4):573–586. 

13.Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic Opioid Use and Central Sleep Apnea: A Review of the Prevalence, Mechanisms, and Perioperative Considerations. Anesthesia & Analgesia. 2015;120(6):1273–1285. 

14.Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018;87:234–244. 

15.Cao M, Javaheri S. Effects of Chronic Opioid Use on Sleep and Wake. Sleep Medicine Clinics. 2018;13(2):271–281. 

16.Chowdhuri S, Wiitala W, Ratz D, Davis J. Sleep Apnea and Prescription Opioid Use in U.S. Veterans: Results from a National Database. B63. My Way: OSA Outpatient Models of Care: American Thoracic Society; 2016:A4182. 

Anesthesia providers are responsible for delivering anesthesia and analgesia in many contexts, ranging from perioperative to critical care.¹ Some anesthesiology professionals focus their practices on treating chronic pain, such as migraine headaches, back pain or pain related to conditions like cancer or fibromyalgia.¹ Approaches to chronic pain management can include ablative techniques to destroy nerves, acupuncture, nerve blocks, botulinum toxin (Botox) injections to relax muscles, electrical nerve stimulation, epidural or intrathecal drug therapies, local anesthetics, minimally invasive surgeries, pharmacologic management, physical therapy, psychologic treatment or trigger point injections.² One approach to chronic pain is iontophoretic drug delivery, which is a noninvasive strategy to manage soft tissue pain.³ In order to provide the best chronic pain care to their patients, clinicians should understand the mechanisms of iontophoresis and its applications in anesthesiology. 

Iontophoresis is defined as the facilitation of ions across a membrane.⁴ It is a form of transdermal drug delivery that uses electrical current to push ionized drugs through the skin’s outer layer, known as the stratum corneum.³ The stratum corneum serves as the body’s first barrier from the external environment and its functions include mechanical reinforcement, protection of cells from ultraviolet (UV) damage, regulation of immune system-regulated inflammation and hydration maintenance.⁵ Though these functions help protect the body, they also prevent the types of molecules that can penetrate the skin.⁶ Iontophoresis uses an electric current to drive hydrophilic and charged molecules through the skin barrier.⁶ This current can be achieved using either a positive or negative electrode, depending on the charge of the molecule that is meant to cross into the body.⁷ Iontophoresis is advantageous in that it can be used to deliver medications locally without injection.⁸ This is particularly useful for patients with fear of needles or pediatric patients.⁸ Additionally, iontophoresis may be useful for a variety of medications, including antibiotics.^8,9 Research on iontophoresis is conflicting, as some reports argue that iontophoresis does not deliver enough medication to deep enough tissue to be effective.⁸ However, use of iontophoresis in dermatology, ophthalmology, dentistry and physical medicine have brought this drug delivery method to the forefront of scientific exploration.¹⁰ 

Iontophoresis can play various roles in analgesia, including—but not limited to—management of pain related to migraines, surgeries or cancer.¹¹ Iontophoresis has been used for chronic pain treatment for at least 40 years.¹²According to Karpiński, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, ibuprofen, aspirin and indomethacin can be used in iontophoresis to relieve joint pain related to rheumatoid arthritis or other injuries.¹³ When applied iontophoretically, NSAIDs do not cause the usual gastrointestinal irritation that comes with their oral administration.¹³ Japour et al. found that acetic acid iontophoresis helped patients with chronic heel pain,¹⁴ and Osborne and Allison showed that acetic acid iontophoresis was more effective than dexamethasone in relieving pain associated with plantar fasciitis.¹⁵ Meanwhile, Yarrobino et al. found that lidocaine iontophoresis reduced pain in patients with chronic epicondylitis (tennis elbow).¹⁶ Nonetheless, the clinical efficacy of iontophoresis in chronic pain remains inconclusive; some researchers even suggest that pain relief may be due to the direct electric current, rather than the transdermal medications.¹⁷ 

Iontophoretic drug delivery can be employed to deliver a variety of medications across the skin barrier. Iontophoresis works by using an electric current to push charged molecules, such as medications, through the skin. In chronic pain management, iontophoresis can deliver substances ranging from NSAIDs to acetic acid to reduce symptoms. More longitudinal, prospective studies are needed to assess the benefits of iontophoretic drug delivery for pain control. Additionally, researchers should investigate the efficacy of self-powered iontophoretic systems that use biomechanical motions as an energy source. 

1.American Society of Anesthesiologists. Role of Physician Anesthesiologist. When Seconds Count… Physician Anesthesiologists Save Lives 2020; https://www.asahq.org/whensecondscount/anesthesia-101/role-of-physician-anesthesiologist/. 

2.Rosenquist RW, Benzon HT, Connis RT, et al. Practice Guidelines for Chronic Pain Management: An Updated Report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2010;112(4):810–833. 

3.Marovino T, Graves C. Iontophoresis in Pain Management. Practical Pain Management. February 21, 2011;8(2). 

4.Daly SM. Biophotonics for blood analysis. In: Meglinski I, ed. Biophotonics for Medical Applications: Woodhead Publishing; 2015:243–299. 

5.Murphrey MB, Miao JH, Zito PM. Histology, Stratum Corneum. StatPearls. Web: StatPearls Publishing LLC; October 30, 2019. 

6.Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Advanced Drug Delivery Reviews. 2004;56(5):619–658. 

7.Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E. General and ocular pharmacology. In: Forrester JV, Dick AD, McMenamin PG, Roberts F, Pearlman E, eds. The Eye (Fourth Edition): W.B. Saunders; 2016:338–369.e331. 

8.Merrick MA. Therapeutic Modalities As an Adjunct to Rehabilitation. In: Andrews JR, Harrelson GL, Wilk KE, eds. Physical Rehabilitation of the Injured Athlete (Fourth Edition). Philadelphia: W.B. Saunders; 2012:104–142. 

9.Mohammed MI, Makky AMA, Teaima MHM, Abdellatif MM, Hamzawy MA, Khalil MAF. Transdermal delivery of vancomycin hydrochloride using combination of nano-ethosomes and iontophoresis: In vitro and in vivo study. Drug Delivery. 2016;23(5):1558–1564. 

10.Nayak AK, Dey S, Pal K, Banerjee I. Iontophoretic drug delivery systems. In: Pal K, Kraatz H-B, Khasnobish A, Bag S, Banerjee I, Kuruganti U, eds. Bioelectronics and Medical Devices: Woodhead Publishing; 2019:393–420. 

11.Pontrelli G, Lauricella M, Ferreira JA, Pena G. Iontophoretic transdermal drug delivery: A multi-layered approach. Mathematical Medicine and Biology: A Journal of the IMA. 2016;34(4):559–576. 

12.Csillik B, Knyihar-Csillik E, Szucs A. Treatment of chronic pain syndromes with iontophoresis of vinca alkaloids to the skin of patients. Pain. 1983;16(2):212. 

13.Karpiński TM. Selected Medicines Used in Iontophoresis. Pharmaceutics. 2018;10(4):204. 

14.Japour C, Vohra R, Vohra P, Garfunkel L, Chin N. Management of heel pain syndrome with acetic acid iontophoresis. Journal of the American Podiatric Medical Association. 1999;89(5):251–257. 

15.Osborne HR, Allison GT. Treatment of plantar fasciitis by LowDye taping and iontophoresis: Short term results of a double blinded, randomised, placebo controlled clinical trial of dexamethasone and acetic acid. British Journal of Sports Medicine (BJSM). 2006;40(6):545–549. 

16.Yarrobino TE, Kalbfleisch JH, Ferslew KE, Panus PC. Lidocaine iontophoresis mediates analgesia in lateral epicondylalgia treatment. Physiotherapy Research International. 2006;11(3):152–160. 

17.Press JM, Bergfeld DA. Physical Modalities. In: Frontera WR, Herring SA, Micheli LJ, Silver JK, Young TP, eds. Clinical Sports Medicine. Edinburgh: W.B. Saunders; 2007:207–226. 

 

The healthcare field has recently seen changes in drug delivery systems as a result of a movement to improve the efficacy of existing systems while lowering side effects [1].Drug delivery systems are useful in delivering the required amount of drugs efficiently to specific target sites. This allows them to increase bioavailability and absorption of molecules, sustain levels for long-term treatment, and decrease the total amount of drugs and doses required for patients, as well as the damage to normal tissues [1].

Intranasal delivery allows direct delivery to the cerebrospinal fluid conveniently and painlessly, with hardly any loss in bioavailability [2]. This is because most anesthetics can easily pass through the mucous membrane, and nasal delivery allows a way for them to completely bypass the blood-brain barrier [2, 3].

Pulmonary drug delivery systems include metered dose inhalers, nebulizers, and dry powder inhalers, which all offer the advantages of larger surface area and proximity to blood flow [4]. There has been a strong effort to develop a way to deliver opioids by inhalation, which has the benefit of increasing patient compliance, since the doses would be lower and less burdensome [1].

Buccal mucosal delivery systems, which consist of drug absorption through the membrane in the inner lining of the cheeks and the bottom of the mouth, are beneficial because they allow drugs to avoid being metabolized through the “first pass effect,” therefore decreasing the amount of the drugs that are needed [5]. While it generally has a slower onset because the buccal mucous is less permeable, it has been proven effective in delivering fentanyl and buprenorphine hydrochloride [6].

Intra-articular drug delivery systems, referring to delivery in the tissue between joints, are thought to prolong the residence time of drugs because of the presence of microspheres that are designed to improve uptake in these areas [7].

Transdermal delivery systems, patches worn on the skin, have been shown to bypass the first pass effect, keep drug levels relatively constant, and decreases gastrointestinal side-effects [1, 8].  After application of a patch, the skin underneath absorbs the drugs and it concentrates in the upper skin levels, gradually diffusing through the skin’s membranes and entering the body [9]. A disadvantage of this system is that only lipophilic, low molecular weight drugs can pass through the skin, but by incorporating enhancers and active energy-dependent methods into the system, dermal anesthesia with hydrophobic substances like lignocaine has been achieved [10].

New molecules with semi-permeable membranes have been developed as carriers that can better target specific tissues and increase absorption rate [1]. Liposomes are nanovesicles that are surrounded by a membrane and are nontoxic, biodegradable, and nonimmunogenic – thus they are promising carriers for drug delivery [11].  However, because of a lot of quality assurance and costs, they have made little strides in clinical practice [12].

Computerized drug delivery systems have been developed inter-disciplinarily, in an attempt to utilize technology to optimize patient care. The advent of these systems, which can be either open-loop or closed-loop, has created a shift towards total intravenous anesthesia [1].  Open-loop systems are known as target-controlled infusion pumps, in which drug concentrations are calculated using a computer and pharmacokinetic models, and the TCI pumps gradually decrease or increase the rate of infusion to meet the desired drug concentration set by an anesthesiologist [1, 13].  Closed-loop systems monitor a patient’s variables such as muscle relaxation, hypnosis, and analgesia in real-time, while a computer-controlled feedback mechanism delivers drugs based on these parameters [14].  This type of computerized system is being developed as a way to provide anesthesia in distant locations, known as tele-anesthesia [15].

References

1. Sona Dave, Deepa Shriyan, and Pinakin Gujjar: New drug delivery systems in anesthesia. J Anaesthesiol Clin Pharmacol. 2017 Apr-Jun; 33(2): 157–163.

2. Talegaonkar S, Mishra PR. Intranasal delivery: An approach to bypass the blood brain barrier. Indian J Pharmacol. 2004;36:140–7

3. Sakane T, Akizuki M, Yoshida M, Yamashita S, Nadai T, Hashida M, et al. Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity. J Pharm Pharmacol. 1991;43:449–51

4. Shaikh S, Nazim S, Khan T, Shaikh A, Zameeruddin M, Quazi A. Recent advances in pulmonary drug delivery system: A review. Int J Appl Pharm. 2010;2:27–31.

5. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. J Pharm Pharm Sci. 1998;1:15–30

6. Gilhotra RM, Ikram M, Srivastava S, Gilhotra N. A clinical perspective on mucoadhesive buccal drug delivery systems. J Biomed Res. 2014;28:81–97

7. Zhang Z, Huang G. Intra-articular lornoxicam loaded PLGA microspheres: Enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis. Drug Deliv. 2012;19:255–63

8. Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb AL. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1:109–31

9. Viscusi ER, Reynolds L, Tait S, Melson T, Atkinson LE. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: A double-blind, placebo-controlled trial. Anesth Analg. 2006;102:188–94

10. Polat BE, Blankschtein D, Langer R. Low-frequency sonophoresis: Application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin Drug Deliv. 2010;7:1415–32

11. Bergese SD, Ramamoorthy S, Patou G, Bramlett K, Gorfine SR, Candiotti KA. Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. J Pain Res. 2012;5:107–16

12. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286

13. Schnider TW, Minto CF, Struys MM, Absalom AR. The safety of target-controlled infusions. Anesth Analg. 2016;122:79–85

14. Glen JB. The development of ‘Diprifusor’: A TCI system for propofol. Anaesthesia. 1998;53(Suppl 1):13–21

15. Hemmerling TM. Automated anesthesia. Curr Opin Anaesthesiol. 2009;22:757–63