Treatment Options

Amoxicillin is a broad spectrum bacteriocidal antibiotic that works by inhibiting cell wall synthesis. Amoxicillin can be taken with or without food. This is a medicine that requires 3x daily dosing; it is important to maintain frequent dosing in order to keep the blood levels of the antibiotic high enough to be effective. Amoxicillin is often prescribed to children under age 8 and to pregnant women who get Lyme disease. Augmentin is a combination medication that includes both amoxicillin and the enzyme inhibitor clavulanate that allows the amoxicillin to be more effective against other penicillin-resistant microbes; a downside of this combination is that it might cause significantly more gastrointestinal disturbance than plain amoxicillin. Most studies have found plain amoxicillin to be highly effective against Borrelia burgdorferi and thus the combination (Augmentin) is not needed.

• Note: If you are allergic penicillin or to cephalosporins, then there is a good chance you may develop an allergic reaction to amoxicillin. A severe allergic reaction known as anaphylaxis is a medical emergency that requires immediate attention.

Cefuroxime, a bacteriocidal 2nd generation cephalosporin, is FDA approved for the treatment of early Lyme disease. Cefuroxime works by disrupting cell wall synthesis and does cross the blood brain barrier to some extent. (The term “generation” when applied to cephalosporins simply refers to when the drug was developed and generally means that the “later” generation versions have a longer half-life (so they don’t need to be taken as frequently) and have better efficacy and safety.) Cefuroxime should be taken with food in twice daily dosing.

• Note: if one is penicillin allergic, there may be an increased risk of developing an allergic reaction to cefuroxime.

Doxycycline is considered the first-line drug of choice for Lyme disease by most physicians. Doxycycline, a bacteriostatic antibiotic, has the advantage of twice daily dosing and effectiveness not only for Lyme disease but also for some other tick-borne diseases such as borrelia miyamotoi disease, ehrlichiosis, anaplasmosis, tularemia, and rocky-mountain spotted fever. In Europe, doxycycline is considered to have comparable efficacy for neurologic Lyme disease as intravenous ceftriaxone; this has not yet been examined in the United States however and may not apply to U.S. neurologic Lyme disease as the genospecies causing neurologic Lyme in the US is B.burgdorferi while in Europe it is most commonly caused by B.garinii. Doxycycline absorption is decreased by food and milk and especially decreased by antacids or laxatives that contain calcium, magnesium, or aluminum or vitamins that contain iron. The latter medications or vitamins should be taken 6 hours before or 2 hours after the doxcycline.

• Note 1: Doxycycline raises the risk of sunburns due to increased skin sensitivity to sunlight. Doxycycline side effects include moderate to severe gastric symptoms (nausea, vomiting, diarrhea), vaginal yeast infections, decreased effectiveness of birth control pills, and rarely liver damage or esophagitis. Doxycycline should not be combined with the acne drug isotretinoin as that will increase the risk of elevated intracranial pressure (and the potential for vision loss).
• Note 2: Use of any tetracycline-class agent (like doxycycline) with alcohol may lead to a bad reaction with symptoms such as headaches, nausea, vomiting, confusion, and flushing.
• Note 3: Doxycycline is contra-indicated in pregnancy. Previously its use was discouraged in children under age 8, but the American Academy of Pediatrics has recently revised their guidelines to allow use.
• Note 4: Patients on blood thinners (anti-coagulants) should be aware that doxycycline can lead to an enhancement of the anti-coagulant effect, possibly increasing the risk of bleeding. The impact of anti-coagulants while on doxycycline should be monitored by the health care provider.

Ceftriaxone is a third generation cephalosporin and, like other cephalosporins, is bacteriocidal. Individuals with neurologic Lyme disease, cardiac Lyme disease, or Lyme arthritis that hasn’t responded well to oral antibiotic treatment will often be given intravenous ceftriaxone. Ceftriaxone has excellent penetration of the blood-brain barrier and is one of the most effective drugs for Lyme disease. Ceftriaxone is typically given once a day intravenously, typically in 45 minutes. While this can be administered in the doctor’s office on a daily basis through a peripheral vein, most commonly it is administered through a mid-line or a PICC line that once inserted can be accessed for the daily infusions at home (thereby eliminating the discomfort and inconvenience of daily needle sticks).

• Note 1: Ceftriaxone can result in biliary sludging that in some patients leads to biliary stones and need for gall bladder removal; in our research study, one patient of 37 developed biliary stones ( 2.7%) which is similar to what has been reported in the literature. Some doctors prescribe “Actigall” to dissolve biliary stone formation, especially if the patient is starting to complain of epigastric pain or nausea. Some doctors order an ultrasonogram of the gall bladder prior to initiating ceftriaxone therapy to identify those patients who might be at greatest risk of forming gall stones.
• Note 2: While the ease of administration is enhanced when ceftriaxone is administered intravenously through a Mid-line or a PICC line, the presence of this indwelling line also increases the risk of systemic infection and serious blood clots. Therefore, patients need to remember to flush their PICC or Mid-line daily, to keep the PICC line site clean, and to not engage in “jerky” arm movements, such as might occur when washing windows or playing tennis or golf. In the evaluation of the patient prior to insertion of a PICC line or a Mid-Line, the clinician orders blood tests to determine if the patient is at higher risk of forming blood clots or inquires about one’s family history of blood clotting.
• Note 3: Rarely ceftriaxone can trigger hemolytic anemia and pancreatitis.
• Note 4: Cefotaxime (Clarforan) is also a 3rd generation intravenous antibiotic. While Cefotaxime is less likely to cause gallstones, it requires 3x daily dosing which for most patients is too difficult to maintain. Given that it is essential for efficacy that the drug be administered every 8 hours, cefotaxime is less commonly used than ceftriaxone.

Benzathine Penicillin is an intramuscular form of penicillin that has the advantage of being long-acting and allowing for consistently high blood and tissue levels of penicillin. Early studies indicated that it was helpful for neurologic Lyme disease, but not nearly as effective as intravenous ceftriaxone (Rocephin). The blood levels after benzathine penicillin are almost as high as after IV ceftriaxone. Because of the intramuscular administration, the risk of gastrointestinal side effects and yeast infections are lower than with oral antibiotics. This is typically given 2-3x week. The medication should be kept refrigerated.

• Note: In most individuals Bicillin is self-administered, often in the muscle of the buttocks. A lidocaine-like anesthetic cream can be applied topoically30-60 minutes before to reduce the injection site pain. The downside to benzathine penicillin is that many people do not want to inject themselves. Because once injected, it can’t be removed, it is important to make sure the individual is not allergic to this medication before initiating treatment.

Azithromycin and clarithromycin are macrolide antibiotics that have been studied in humans for the treatment of Lyme disease. Both are better tolerated than the older macrolide antibiotic erythromycin in having fewer gastrointestinal side effects. Both azithromycin and clarithromycin are considered second-line agents for Lyme disease among individuals who cannot tolerate doxycycline, amoxicillin, or cefuroxime. (Erythromycin is considered inferior to the other first line agents such as doxycycline or amoxicillin and is therefore not recommended as a primary agent for Lyme disease.)  In addition to their benefits as antimicrobial agents, azithromycin and clarithromycin also have anti-inflammatory properties that can lead to symptom improvement.   There are study design problems with the research studies of azithromycin and clarithromycin; therefore, it is hard to know whether they are truly less efficacious than the first-line agents for early Lyme disease.  

        Macrolides however should be used with caution given the risk of interaction with other medications.  The key to consider is that these antibiotics impact the liver enzymes that help to metabolize other medications; specifically they can affect the cytochrome P450 1A2 and 3A4 isoenyzmes.  Because of this, drug-drug interactions can occur.  For example, erythromycin or clarithromycin can lead to dangerously increased blood levels of the anticonvulsant drug carbamazepine (Tegretol) as well as increases in the anti-anxiety drug alprazolam (Xanax). Erythromycin and clarithromycin can also lead to an increase in the blood levels of the anti-asthmatic drug, theophylline, which can put the patient at risk for seizures or arrhythmias.  When macrolides are used with paroxetine (Paxil) – an anti-depressant drug, there may be an unexpected increase in the blood level of the parosetine due to the macrolide-inducted inhibition of the liver enzyme metabolism; this could lead to mania or serotonin syndrome.  

Neuropathic pain (numbness, tingling, burning, shooting) and central "brain" pain syndromes can often be helped with agents such as gabapentin ("Neurontin") or pregabalin ("Lyrica"). There was a small open label trial that showed that gabapentin was quite helpful in reducing neuropathic pain for a group of Lyme patients complaining of persistent fatigue (Weissenbacher 2005).

Neuropathic, muscular, and arthritic pain can often be helped with agents such as amitriptyline, cyclobenzaprine, or SNRIs (e.g., duloxetine (Cymbalta), milnacipran (Savella), venlafaxine (Effexor)). The SNRIs are particularly useful for patients with persistent Lyme-related symptoms as they are quite effective for reducing pain as well as for improving mood and decreasing anxiety. It should be noted however that to obtain the pain relief from a medication such as venlafaxine, in most patients the dose needs to be increased to 225-300 mg/day in order to obtain the benefits for pain and mood.

Neuropathic pain that has an autoimmune etiology (possibly triggered by the prior infection with B.burgdorferi) may benefit from treatment with intravenous gammaglobulin therapy .

Musculoskeletal pain may be helped by low-dose naltrexone, as 2 published trials have reported benefit in fibromyalgia.

Arthritic pain that persists after antibiotic therapy may be reduced by nonsteroidal anti-inflammatory drugs (NSAIDS) that reduce inflammation. Beware however that long-term use of NSAIDS increases the risk of gastric ulcers and kidney damage. For patients whose arthritis is not helped by NSAIDS, published reports indicate that methotrexate or hydroxychloroquine can be helpful; these are called disease-modifying anti-rheumatic drugs.

• Mindfulness meditation and Yoga can reduce stress and pain and enhance energy. We will have a research study that examines the use of meditation and Yoga for patients with persistent fatigue and pain after antibiotic treatment for Lyme disease.
• Mind-body practices. Qigong is a mind-body-spirit practice that integrates posture, movement, breathing technique, self-massage, sound, and focused attention. In one randomized controlled trial, fatigue and mental functioning were significantly improved in the experimental group compared to the wait-list controls.
• Neurofeedback may be helpful in improving pain, as well as in improving sleep and attention. This has been studied for migraines, fibromyalgia, and ADHD.

Ensure quality sleep of seven to eight hours per night. Undiagnosed sleep disorders need to be ruled-out (e.g, sleep apnea). Because fatigue can be a prominent symptom of depression, it is important to ensure a low-grade depression hasn't gone untreated.

• Bupropion is an anti-depressant agent that boosts norepinephrine and dopamine and tends to improve mood, energy, and cognitive focus. Onset of improvement is usually seen after two to four weeks of daily treatment.
• Modafinil (Provigil) or Armodafinil (Nuvigil) are both wakefulness promoting agents that have been reported to help fatigue in other diseases.
• Acupuncture has been studied as a treatment for fatigue, primarily in China. In a randomized, sham-controlled trial of acupuncture of 127 individuals diagnosed with "chronic fatigue syndrome" (two sessions per week for four weeks), the acupuncture group showed moderately large reductions in physical and mental fatigue.
• Mindfulness meditation and Yoga can reduce stress and pain and enhance energy. We will have a research study that examines the use of meditation and Yoga for patients with persistent fatigue and pain after antibiotic treatment for Lyme disease. 
• Mind-body practices. Qigong is a mind-body-spirit practice that integrates posture, movement, breathing technique, self-massage, sound, and focused attention. In one randomized controlled trial, fatigue and mental functioning were significantly improved in the experimental group compared to the wait-list controls.

Poor sleep can lead to daytime fatigue, impaired cognition, and musculoskeletal pain. Clinicians should ask the patient about sleep behaviors, as poor sleep hygiene can induce insomnia. Undiagnosed sleep disorders should be ruled out, including restless leg syndrome, narcolepsy, sleep apnea. Avoid substances that would impair sleep (e.g., alcohol, appetite suppressants, caffeine). Improving sleep hygiene is the best approach for insomnia. However, when behavioral changes don't work, pharmacologic therapies should be considered.

• Cognitive behavior therapy and relaxation techniques (e.g., mindfulness; stretching) can be helpful
• Lemon balm and melatonin: While there are many supplements that people use to help with sleep as alternatives to conventional sleep medications, the ones considered safe that are commonly used include lemon balm and melatonin. The botanical lemon balm (Melissa officinalis) has not been well-studied but open label trials suggest it is helpful in reducing anxiety and improving sleep. Neither lemon balm nor melatonin are considered safe in pregnancy. Some concerns exist about whether melatonin may exacerbate autoimmune illness.
• Medications: Certain medications can help both sleep and reduce pain. These include low doses of amitriptyline, cyclobenzaprine, and doxepin. Low doses of mirtazipine, trazodone, or quetiapine may also improve sleep onset and duration. Gabepentin can help to improve sleep as well as reduce nerve pains and restless leg syndrome. Short-acting medications are best for people complaining of delayed sleep onset (e.g, zolpidem, lorazepam, ramelteon). Longer-acting medications can be helpful for those who report a hard time maintaining sleep (long acting zolpidem, temazepam, eszopiclone, low dose doxepin, low dose trazodone)
  • Note: suvorexant ("Belsomra") is not recommended for patients being treated for Lyme disease as it can interact with many medications used by infectious disease doctors. It is not recommended for people who are on medications that inhibit the liver enzyme CYP3A such as clarithromycin ("Biaxin") or ketoconazole ("Nizoral") or fluconazole ("Diflucan") or erythromycin.
• Neurofeedback may be helpful in improving sleep, as well as in improving attention and reducing pain. This has been studied for migraines, fibromyalgia, and ADHD.

Both psychotherapy and pharmacotherapy have proven benefits for improving mood. Psychotherapy has many different types — such as supportive, dynamic, cognitive behavioral, dialectical behavior therapy, transference focused psychotherapy — each of which offers benefit. Pharmacotherapy also has many different types. For depression the first-line options usually are SSRIs, SNRIs, Tricyclics or other agents with more unique modes of action.

A few noteworthy tips on anti-depressant agents:

• Most anti-depressant agents also help in reducing anxiety. However the opposite isn't necessarily true. Specific anti-anxiety agents such as clonazepam or diazepam may not necessarily help fight depression.
• Most anti-depressants take three to eight weeks before an effect is seen. Therefore, it is unwise to stop an anti-depressant after only three or four weeks, as staying on it another two to three weeks may lead to a good response.
• Dosage makes a difference. Some anti-depressants work fine at low doses; some medications however are effective only at higher doses. Some medications are more effective as the dose is increased. Other antidepressants (such as the tricyclic antidepressants) may have a therapeutic range — one has to achieve at least a certain dosage (to get to the right blood level).

Improving memory is a challenge. In Lyme disease, short-term memory problems and word-retrieval problems are common. These often improve substantially with appropriate antibiotic therapy. Over time, most patients regain their cognitive function.

When memory is a problem, consider that this could be due to a primary problem with attention or with mood. An individual who can't focus won't be able to remember because he/she didn't "attend" to the item in the first place. This happens to all of us when we hear someone's name at a party; if we don't focus on the name and perhaps make a mental association to the name to enhance memory storage, we will forget that name within minutes. Patients with depression often experience problems with memory and verbal fluency; when the depression is resolved, the memory and verbal fluency typically resolve as well.

• Medications: Attention can be improved with certain medications, such as bupropion ("Wellbutrin"), atomoxetine ("Strattera"), modafinil ("Provigil"), or stimulants (e.g., methylphenidate). Medications that temporarily slow cognitive decline in Alzheimer's disease (e.g., donepezil ("Aricept") or memantine ("Namenda")) have not been studied in Lyme disease.
• There is some evidence that online brain training programs (e.g., www.cogmed.com or www.brainhq.com) can enhance concentration (working memory) or processing speed.
• Neurofeedback may be helpful in improving attention, as well as in improving sleep and reducing pain. This has been studied for migraines, fibromyalgia, and ADHD.